Orally available compounds, a process for preparing the same and their uses as anti-adhesive drugs for treating e. coli induced inflammatory bowel diseases such as crohn&#39;s disease

ABSTRACT

Orally available compounds, a process for preparing the same and their uses as anti-adhesive drugs for treating  E. coli  induced inflammatory bowel diseases such as crohn&#39;s disease.

The present invention relates to orally available compounds, a processfor preparing the same and their uses as anti-adhesive drugs fortreating E. coli induced inflammatory bowel diseases such as crohn'sdisease.

Crohn's disease is a chronic and lifelong disease which affects 4millions of people worldwide with a prevalence of about 100 cases per100,000 individuals. It has a major impact on the quality of life,extending into the old age and 80% of patients will require surgery.Crohn's disease represents an important economic impact on thehealthcare system and the economy as a whole, with direct costs($18,022-18,932 per year for patients living in the US, “Inflammatorybowel disease-attributable costs and cost-effective strategies in theunited states: a review” K. T. Park, Md., and Dorsey Bass, Md., IBD2011) and indirect costs because of the effect on employability.

Crohn's disease is characterized by an aberrant immune responseoccurring in a genetically predisposed host in response to microbesand/or microbial compounds. Adherent-Invasive E. coli (AIEC) bacteriaare found abnormally associated with the ileal mucosa in 36.4% of theCrohn's disease patients with an ileal involvement. As these bacteriapossess invasive, anti-phagocytic and pro-inflammatory properties, thisis of a crucial importance to elaborate a strategy to eradicate AIECbacteria from the digestive tract, in inhibiting the bacterial adhesion.The role of type 1 fimbriae was well established in these E. colistrains associated with Crohn's disease. It has been shown that theileum of CD patients is abnormally colonized by E. coli bacteria inresults from overexpression of carcinoembryonic antigen-related celladhesion molecule 6 (CEACAM6) acting as receptors for E. coli adhesionvia type 1 pili. Bacterial adhesion to intestinal epithelial cells ismediated by the FimH adhesin on the tip of the type 1 pili from thebacteria. Several amino acid substitutions modify type 1 pili FimHadhesin affinity for various mannose residues (Bouckaert, Berglund,Schembri, Christiansen and Klemm, FimH-mediated autoaggregation ofEscherichia coli. Mol Microbiol, 2001. 41.1419-30, Sokurenko, Schembri,Trintchina, Kjaergaard, Hasty and Klemm, Valency conversion in the type1 fimbrial adhesin of Escherichia coli. Mol Microbiol, 2001. 41.675-86),under conditions of shear force. The AIEC reference strain LF82expresses type 1 pili variant with four amino acid substitutions (V27A;N705; S78N; T158P) that could favour the binding of the bacteria to theabnormally expressed CEACAM6 receptor in CD patients. The host/bacteriacrosstalk in the context of host susceptibility to CD can be mimickedusing CEABAC10 transgenic mouse expressing human CEACAM6 receptor. Inthis model, it has been reported that AIEC infected CEABAC10 micedevelop severe colitis and are abundantly colonized by bacteria onlywhen AIEC bacteria express type 1 pili.

The specificity of FimH lectin has been identified by Bouckaert(Bouckaert, J. et al., Mol. Microbiol. 2006, 61(6), 1556-68) and Wellenset al., (Wellens, A. et al., PloS One 2008, 3(4), e2040). The FimHadhesin has been structurally and functionally characterized and aseries of inhibitors with nanomolar afinities has been developed(Bouckaert, J., Berglund, J. et al. Mol. Microbiol. 2005, 55(2), 441-55;Gouin, S. G. et al., ChemMedChem. 2009, 5, 749-755). It has beendemonstrated that alkyl α-D-manoside are effectively inhibiting bindingof E. coli to its human cell targets (US2008171706). Heptylα-D-mannoside (HM) is still one of the best monomeric mannose-basedinhibitors of FimH to date in vitro.

However, HM is ineffective in vivo, probably due to its amphiphilicnature, allowing its insertion in biological membranes.

One objective of the present invention is to provide monomeric mannosederivatives liable to constitute a treatment of pathologies induced bytype 1 fimbriated E. coli, in particular inflammatory bowel disease,more particularly Crohn's disease.

Another aim of the present invention is to provide monomeric mannosederivatives being active in vivo towards inflammatory bowel disease,especially Crohn's disease.

Still another aim of the present invention is to provide monomericmannose derivatives, which are able to be administrated per os.

The present invention relates to a compound of the following formula(I):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O or S;-   R representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular methyl, ethyl,        isopropyl or isobutyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,    -   a cyclodextrin, said cyclodextrin being in particular chosen        from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD),        γ-cyclodextrin (γ-CD) and their derivatives, in particular        alkylated α-cyclodextrins, alkylated β-cyclodextrins and        alkylated γ-cyclodextrins, said cyclodextrin being more        particularly β-cyclodextrin, even more particulary        β-cyclodextrin of the following formula:

said (C₁-C₇)-alkyl, (C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl,(C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,(C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin beingsubstituted or not by one or more substituent(s), each independentlyselected from:

-   -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN;

-   provided that when R represents CHRa-NH₂, then Y can only represent    the following group (a):

for use in the treatment or the prevention of inflammatory boweldisease, in particular Crohn disease or ulcerative colitis.

The present invention also relates to a compound of the followingformula (I):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O, S or NH;-   R representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular methyl, ethyl,        isopropyl or isobutyl,    -   a group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H, wherein X′        represents O, S or NH, i is an integer from 1 to 7, and j is an        integer from 0 to 7, said group being in particular —CH₂—O—CH₃,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,    -   a cyclodextrin, said cyclodextrin being in particular chosen        from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD),        γ-cyclodextrin (γ-CD) and their derivatives, in particular        alkylated α-cyclodextrins, alkylated β-cyclodextrins and        alkylated γ-cyclodextrins, said cyclodextrin being more        particularly a β-cyclodextrin, even more particulary a        cyclodextrin of one of the following formulae:

said (C₁-C₇)-alkyl, group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H,(C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl, (C₃-C₇)-cycloalkyl,(C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,(C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin beingsubstituted or not by one or more substituent(s), each independentlyselected from:

-   -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN,    -   SO₃H or one of its salts, in particular SO₃Na;

-   and its pharmaceutically acceptable salts,

-   provided that when R represents CHRa-NH₂, then Y can only represent    the following group (a):

for use in the treatment or the prevention of inflammatory boweldisease, in particular Crohn disease or ulcerative colitis.

By linear (C₁-C₇) alkyl group is meant a group such as methyl, ethyl,propyl, butyl, pentyl, hexyl or heptyl.

By branched alkyl group is meant an alkyl group as defined above bearingsubstituents selected from the list of linear alkyl groups definedabove, said linear alkyl group being also liable to be branched.

By linear (C₂-C₇) alkenyl group is meant a linear hydrocarbon groupconstituted by 2 to 7 carbon atoms, with one or more carbon-carbondouble bond(s).

By branched alkenyl group is meant an alkenyl group as defined abovebearing substituents selected from the list of linear alkyl groupsdefined above, said linear alkyl group being also liable to be branched.

By linear (C₂-C₇) alkynyl group is meant a linear hydrocarbon groupconstituted by 2 to 7 carbon atoms, with one or more carbon-carbontriple bond(s).

By branched alkynyl group is meant an alkynyl group as defined abovebearing substituents selected from the list of linear alkyl groupsdefined above, said linear alkyl group being also liable to be branched.

By (C₃-C₇)-cycloalkyl group is meant a group such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

By (C₅-C₇)-cycloalkenyl group is meant a cyclic hydrocarbon groupconstituted by 5 to 7 carbon atoms, with one or more carbon-carbondouble bond(s).

By (C₃-C₇)-heterocycloalkyl group is meant a (C₃-C₇)-cyclic group havingat least one non-carbon atom in the ring.

By (C₅-C₇)-heterocycloalkenyl group is meant a heterocyclic groupconstituted by 5 to 7 carbon atoms, with one or more double bond(s).

The term “aryl” refers to any functional group or substituent derivedfrom a simple aromatic ring, aforesaid aromatic ring comprising from 6to 16 carbon atoms.

The term “heteroaromatic” refers to a compound comprising from 5 to 16atoms, having the characteristics of an aromatic compound whilst havingat least one non-carbon atom in the ring, aforesaid non-carbon atombeing in particular N, S or O.

By alkyl aryl group is meant a linear or branched alkyl group as definedabove, which is substituted by an aryl group.

By

is meant that the atom At is bound through a covalent bond to anotheratom or group that is not represented.

For instance, considering:

by

is meant that the oxygen atom is bound to another atom or group througha covalent bond involving aforesaid oxygen atom.

By “proteinogenic amino acid” is meant amino acids that are precursorsto proteins, such as alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, pyrrolysine,selenocysteine, serine, threonine, tryptophan, tyrosine and valine.

By “side chain of an aminoacid” is meant the group S_(c) as definedhereafter: H₂NCHS_(c)COOH.

The amino acid residue of formula —CHRa—NH₂ is of configuration L or D,in particular of configuration L

The above-mentioned definitions apply to the entire specification.

Interestingly, the inventors have found that compounds of the inventionare not only able to inhibit bacterial binding to uroepithelial cells,but also to inhibit bacterial binding to intestinal epithelial cells.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-1), wherein R is R₁,R₁ representing:

-   -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular isopropyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantly,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,

-   R₁ representing in particular:    -   a linear (C₁-C₇)-alkyl, more particularly methyl, ethyl, propyl        or butyl, optionally substituted by a —OH and/or a —NH₂ group,    -   a branched (C₃-C₇)-alkyl, more particularly isopropyl or        isobutyl,    -   a (C₃-C₇)-heterocycloalkyl, more particularly a pyrrolidine,    -   an aryl, said aryl being an aromatic or heteroaromatic group,        more particularly a phenyl, a pyridinyl, a pyrrole or an        imidazole, optionally substituted by a —OH, a —NH₂ or a —SO₃Na        group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group, more particulary a benzyl, a phenethyl or an ethyl        imidazolyl, optionally substituted by a —OH or a —NH₂ group,    -   CHRa—NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid, in particular alanine, serine, proline,        phenylalanine, cysteine or histidine.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-1), wherein R is R₁,R₁ representing:

-   -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular isopropyl,    -   a group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H, wherein X′        represents O, S or NH, i is an integer from 1 to 7, and j is an        integer from 0 to 7, said group being in particular —CH₂—O—CH₃,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantly,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,

-   R₁ representing in particular:    -   a linear (C₁-C₇)-alkyl, more particularly methyl, ethyl, propyl        or butyl, optionally substituted by a —OH and/or a —NH₂ group,    -   a group of formula —CH₂—O—CH₃, optionally substituted by a        pyridinyl,    -   a branched (C₃-C₇)-alkyl, more particularly isopropyl or        isobutyl,    -   a (C₃-C₇)-heterocycloalkyl, more particularly a pyrrolidine,    -   an aryl, said aryl being an aromatic or heteroaromatic group,        more particularly a phenyl, a pyridinyl, a pyrrole or an        imidazole, optionally substituted by a —OH, a —NH₂ or a —SO₃Na        group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group, more particulary a benzyl, a phenethyl or an ethyl        imidazolyl, optionally substituted by a —OH or a —NH₂ group,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid, in particular alanine, serine, proline,        phenylalanine, cysteine or histidine.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1), wherein Yrepresents:

of following formula (I-1a):

-   X, R₁ and n being as defined above,-   R₁ representing in particular a linear or branched (C₁-C₇)-alkyl,    more particularly isopropyl.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1), wherein Yrepresents:

of following formula (I-1b):

-   X, R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1), wherein Yrepresents:

of following formula (I-1c):

-   X, Z, R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-2), wherein R is R₂,R₂ representing a cyclodextrin, said cyclodextrin being in particularchosen from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin(γ-CD) and their derivatives, in particular alkylated α-cyclodextrins,alkylated β-cyclodextrins and alkylated γ-cyclodextrins, saidcyclodextrin being more particularly a β-cyclodextrin, even moreparticulary a β-cyclodextrin of the following formula:

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-2), wherein R is R₂,R₂ representing a cyclodextrin, said cyclodextrin being in particularchosen from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin(γ-CD) and their derivatives, in particular alkylated α-cyclodextrins,alkylated β-cyclodextrins and alkylated γ-cyclodextrins, saidcyclodextrin being more particularly a β-cyclodextrin, even moreparticulary a β-cyclodextrin of the following formula:

As indicated above, R is in the case of the formula (I-2) acyclodextrin.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-2), wherein Yrepresents:

of following formula (I-2c):

-   X, R₂, n and Z being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-2c), wherein Xrepresents O or S, in particular S.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-2c), wherein R₂represents:

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-2c), X represents Oor S, in particular S, and wherein R₂ represents:

-   Z being in particular O.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1a-1):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1a-2):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1a-3):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1a-4):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1b-1):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1b-2):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1b-3):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1b-4):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-1):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-2):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-3):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-4):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-5):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-6):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-7):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-8):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1a-1), (I-1a-2),(I-1a-3), (I-1a-4), (I-1b-1), (I-1b-2), (I-1b-3), (I-1b-4), (I-1c-1),(I-1c-2), (I-1c-3), (I-1c-4), (I-1c-5), (I-1c-6), (I-1c-7) or (I-1c-8),wherein R₁ represents:

-   -   a linear (C₁-C₇)-alkyl, more particularly methyl, ethyl, propyl        or butyl, optionally substituted by a —OH and/or a —NH₂ group,    -   a branched (C₃-C₇)-alkyl, more particularly isopropyl or        isobutyl,    -   a (C₃-C₇)-heterocycloalkyl, more particularly a pyrrolidine,    -   an aryl, said aryl being an aromatic or heteroaromatic group,        more particularly a phenyl, a pyridinyl, a pyrrole or an        imidazole, optionally substituted by a —OH, a —NH₂ or a —SO₃Na        group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group, more particulary a benzyl, a phenethyl or an ethyl        imidazolyl, optionally substituted by a —OH or a —NH₂ group,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid, in particular alanine, serine, proline,        phenylalanine, cysteine or histidine.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2a-1):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2a-2):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2a-3):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2a-4):

R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2b-1):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2b-2):

-   R₂ and n being as defined above.-   In an advantageous embodiment of the use according to the invention,    the compound of formula (I-2) is of following formula (I-2b-3):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2b-4):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-1):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-2):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-3):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-4):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-5):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-6):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-7):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-8):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1a-1), (I-1a-2),(I-1a-3), (I-1a-4), (I-1b-1), (I-1b-2), (I-1b-3), (I-1b-4), (I-1c-1),(I-1c-2), (I-1c-3), (I-1c-4), (I-1c-5), (I-1c-6), (I-1c-7), (I-1c-8),(I-2a-1), (I-2a-2), (I-2a-3), (I-2a-4), (I-2b-1), (I-2b-2), (I-2b-3),(I-2b-4), (I-2c-1), (I-2c-2), (I-2c-3), (I-2c-4), (I-2c-5), (I-2c-6),(I-2c-7) or (I-2c-8), wherein n is equal to 5.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I) selected fromthe group consisting of:

and their pharmaceutically acceptable salts.

The compounds according to the present invention may exist in the formof their pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to conventional acid-addition salts orbase-addition salts that retain the biological effectiveness andproperties of the compounds of formula (I) and are formed from suitablenon-toxic organic or inorganic acids or organic or inorganic bases.Acid-addition salts include for example those derived from inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and thosederived from organic acids such as p-toluenesulfonic acid, salicylicacid, methanesulfonic acid, oxalic acid, succinic acid, citric acid,malic acid, lactic acid, fumaric acid, 1-hydroxy-2-naphthoic acid,2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaricacid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid,adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoicacid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoicacid), caproic acid (hexanoic acid), caprylic acid (octanoic acid),carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaricacid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid,glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid,hippuric acid, isobutyric acid, lactobionic acid, lauric acid, maleicacid, malonic acid, mandelic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, palmitic acid,pamoic acid, proprionic acid, pyroglutamic acid, sebacic acid, stearicacid, tartaric acid, thiocyanic acid, trifluoroacetic acid, undecylenicacid, and the like.

Base-addition salts include those derived from ammonium, potassium,sodium and, quaternary ammonium hydroxides, such as for example,tetramethyl ammonium hydroxide.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I) of one of thefollowing formulae:

It is noted that the following compound is active in humans, in thetreatment or the prevention of inflammatory bowel disease, in particularCrohn disease or ulcerative colitis:

In another aspect, the present invention relates to a new compound ofthe following formula (I-0):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O or S;-   R representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular isopropyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,    -   a cyclodextrin, said cyclodextrin being in particular chosen        from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD),        γ-cyclodextrin (γ-CD) and their derivatives, in particular        alkylated α-cyclodextrins, alkylated γ-cyclodextrins and        alkylated γ-cyclodextrins, said cyclodextrin being more        particularly a β-cyclodextrin, even more particulary a        β-cyclodextrin of the following formula:

said (C₁-C₇)-alkyl, (C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl,(C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,(C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin beingsubstituted or not by one or more substituent(s), each independentlyselected from:

-   -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN;

-   provided that when R represents CHRa-NH₂, then Y can only represent    the following group (a):

with the proviso that said compound is not of the following structure:

In another aspect, the present invention relates to a new compound ofthe following formula (I-0):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O, S or NH;-   R representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular methyl, ethyl,        isopropyl or isobutyl,    -   a group of formula —(CH₂)₁—X′—(CH₂)_(j)—H, wherein X′ represents        O, S or NH, i is an integer from 1 to 7, and j is an integer        from 0 to 7, said group being in particular —CH₂—O—CH₃,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,    -   a cyclodextrin, said cyclodextrin being in particular chosen        from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD),        γ-cyclodextrin (γ-CD) and their derivatives, in particular        alkylated α-cyclodextrins, alkylated β-cyclodextrins and        alkylated γ-cyclodextrins, said cyclodextrin being more        particularly a β-cyclodextrin, even more particulary a        cyclodextrin of one of the following formulae:

said (C₁-C₇)-alkyl, group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H,(C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl, (C₃-C₇)-cycloalkyl,(C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,(C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin beingsubstituted or not by one or more substituent(s), each independentlyselected from:

-   -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN,    -   SO₃H or one of its salts, in particular SO₃Na;        and its pharmaceutically acceptable salts, provided that when R        represents CHRa-NH₂, then Y can only represent the following        group (a):

with the proviso that said compound is not of one of the followingstructures:

and its salts.

In an advantageous embodiment, the present invention relates to a newcompound of the following formula (I-1):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer comprised from 3 to 7, n being in particular    equal to 5;-   Y represents a group selected from:

-   Z representing O or S;-   R₁ representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular isopropyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,        said (C₁-C₇)-alkyl, (C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl,        (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl,        (C₃-C₇)-heterocycloalkyl, (C₅-C₇)-heterocycloalkenyl,        CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl, CONH-(C₁-C₇)-alkyl, aryl,        alkyl aryl and CO-aryl being substituted or not by one or more        substituent(s), each independently selected from:    -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN;-   provided that when R₁ represents CHRa-NH₂, then Y can only represent    the following group (a):

In an advantageous embodiment, the present invention relates to a newcompound of the following formula (I-1):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O, S or NH;-   R₁ representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular methyl, ethyl,        isopropyl or isobutyl,    -   a group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H, wherein X′        represents O, S or NH, i is an integer from 1 to 7, and j is an        integer from 0 to 7, said group being in particular —CH₂—O—CH₃,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,        said (C₁-C₇)-alkyl, group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H,        (C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,        (C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,        CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl and CO-aryl being        substituted or not by one or more substituent(s), each        independently selected from:    -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN,    -   SO₃H or one of its salts, in particular SO₃Na;-   and its pharmaceutically acceptable salts,-   provided that when R₁ represents CHRa-NH₂, then Y can only represent    the following group (a):

with the proviso that said compound is not of one of the followingstructures:

and its salts.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-0) or (I-1), wherein R or R₁ represents:

-   -   a linear (C₁-C₇)-alkyl, more particularly methyl, ethyl, propyl        or butyl, optionally substituted by a —OH and/or a —NH₂ group,    -   a branched (C₃-C₇)-alkyl, more particularly isopropyl or        isobutyl,    -   a (C₃-C₇)-heterocycloalkyl, more particularly a pyrrolidine,    -   an aryl, said aryl being an aromatic or heteroaromatic group,        more particularly a phenyl, a pyridinyl, a pyrrole or an        imidazole, optionally substituted by a —OH, a —NH₂ or a —SO₃Na        group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group, more particulary a benzyl, a phenethyl or an ethyl        imidazolyl, optionally substituted by a —OH or a —NH₂ group,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid, in particular alanine, serine, proline,        phenylalanine, cysteine or histidine.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-0), of particular formula (I-2):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O, S or NH;-   R₂ representing a cyclodextrin, said cyclodextrin being in    particular chosen from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD),    γ-cyclodextrin (γ-CD) and their derivatives, in particular alkylated    γ-cyclodextrins, alkylated β-cyclodextrins and alkylated    γ-cyclodextrins, said cyclodextrin being more particularly a    β-cyclodextrin, even more particulary a β-cyclodextrin of the    following formula:

said cyclodextrin being substituted or not by one or moresubstituent(s), each independently selected from:

-   -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN;        with the proviso that said compound is not of the following        structure:

In an advantageous embodiment, the present invention relates to acompound of formula (I-0) or (I-1), wherein Y represents:

of following formula (I-1a):

-   X, R and n being as defined above,-   R being R₁ as defined above when said compound is of formula (I-1),-   R representing in particular a linear or branched (C₁-C₇)-alkyl,    more particularly isopropyl.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1a):

wherein X and n being as defined above,

-   R₁ representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular methyl, ethyl,        isopropyl or isobutyl,    -   a group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H, wherein X′        represents O, S or NH, i is an integer from 1 to 7, and j is an        integer from 0 to 7, said group being in particular —CH₂—O—CH₃,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,        said (C₁-C₇)-alkyl, group of formula —(CH₂)_(i)—X′—(CH_(j)—H,        (C₂-C₇)-alkynyl, (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl,        (C₃-C₇)-heterocycloalkyl, (C₅-C₇)-heterocycloalkenyl,        CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl, CONH-(C₁-C₇)-alkyl, aryl,        alkyl aryl and CO-aryl being substituted or not by one or more        substituent(s), each independently selected from:    -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,        -   at least one of R_(b) and R_(c) representing            CO-(C₁-C₇)-alkyl, or CO-aryl,    -   NO₂,    -   CN,    -   SO₃H or one of its salts, in particular SO₃Na.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-0) or (I-1), wherein Y represents:

of following formula (I-1b):

-   X, n and R being as defined above,-   R being R₁ as defined above when said compound is of formula (I-1).

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-0) or (I-1), wherein Y represents:

-   Z being as defined above,-   of following formula (1-16:

-   X, n, Z and R being as defined above,-   R being R₁ as defined above when said compound is of formula (I-1).

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), wherein Y represents:

of following formula (I-2c):

-   X, R₂, n and Z being as defined above.

In an advantageous embodiment, the new compound of formula (I) is ofparticular formula (I-2c), wherein X represents O or S, in particular S.

In an advantageous embodiment, the new compound of formula (I) is ofparticular formula (I-2c), wherein R₂ represents:

In an advantageous embodiment, the new compound of formula (I) is ofparticular formula (I-2c), X represents O or S, in particular S, andwherein R₂ represents:

-   Z being in particular O.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1a-1):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1a-2):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1a-3):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1a-4):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1b-1):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1b-2):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1b-3):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1b-4):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1c-1):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1c-2):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1c-3):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1c-4):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1c-5):

R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1c-6):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1c-7):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1), of following formula (I-1c-8):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1a-1), (I-1a-2), (I-1a-3), (I-1a-4), (I-1b-1),(I-1b-2), (I-1b-3), (I-1b-4), (I-1c-1), (I-1c-2), (I-1c-3), (I-1c-4),(I-1c-5), (I-1c-6), (I-1c-7) or (I-1c-8), wherein R₁ represents:

-   -   a linear (C₁-C₇)-alkyl, more particularly methyl, ethyl, propyl        or butyl, optionally substituted by a —OH and/or a —NH₂ group,    -   a branched (C₃-C₇)-alkyl, more particularly isopropyl or        isobutyl,    -   a (C₃-C₇)-heterocycloalkyl, more particularly a pyrrolidine,    -   an aryl, said aryl being an aromatic or heteroaromatic group,        more particularly a phenyl, a pyridinyl, a pyrrole or an        imidazole, optionally substituted by a —OH, a —NH₂ or a —SO₃Na        group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group, more particulary a benzyl, a phenethyl or an ethyl        imidazolyl, optionally substituted by a —OH or a —NH₂ group,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid, in particular alanine, serine, proline,        phenylalanine, cysteine or histidine.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2a-1):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2a-2):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2a-3):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2a-4):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2b-1):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2b-2):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2b-3):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2b-4):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2c-1):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2c-2):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2c-3):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2c-4):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2c-5):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2c-6):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2c-7):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-2), of following formula (I-2c-8):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-1a-1), (I-1a-2), (I-1a-3), (I-1a-4), (I-1b-1),(I-1b-2), (I-1b-3), (I-1b-4), (I-1c-1), (I-1c-2), (I-1c-3), (I-1c-4),(I-1c-5), (I-1c-6), (I-1c-7), (I-1c-8), (I-2a-1), (I-2a-2), (I-2a-3),(I-2a-4), (I-2b-1), (I-2b-2), (I-2b-3), (I-2b-4), (I-2c-1), (I-2c-2),(I-2c-3), (I-2c-4), (I-2c-5), (I-2c-6), (I-2c-7) or (I-2c-8), wherein nis equal to 5.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I-0) or (I-1), selected from the group consistingof:

and their salts, in particular their pharmaceutically acceptable salts.

In an advantageous embodiment, the present invention relates to a newcompound of formula (I) of one of the following formulae:

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising, as active substance, a compound of formula (I-0)or (I-1), in particular (I-1a-1), (I-1a-2), (I-1a-3), (I-1a-4),(I-1b-1), (I-1b-2), (I-1b-3), (I-1b-4), (I-1c-1), (I-1c-2), (I-1c-3),(I-1c-4), (I-1c-5), (I-1c-6), (I-1c-7), (I-1c-8), (I-2a-1), (I-2a-2),(I-2a-3), (I-2a-4), (I-2b-1), (I-2b-2), (I-2b-3), (I-2b-4), (I-2c-1),(I-2c-2), (I-2c-3), (I-2c-4), (I-2c-5), (I-2c-6), (I-2c-7) or (I-2c-8),as defined above, in association with a pharmaceutically acceptablevehicle.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising, as active substance, a compound of formula (I)of one of the following formulae:

in association with a pharmaceutically acceptable vehicle.

The expression “pharmaceutically acceptable vehicle” denotes inparticular cellulose, starch, benzyl alcohol, polyethylene glycol,gelatin, lactose, polysorbate, magnesium or calcium stearate, xanthangum, guar, alginate, colloidal silica.

The compositions according to the invention can be used by oral,parenteral, topic, or rectal route or in aerosols.

As solid compositions for oral administration, tablets, pills, gelatincapsules, powders or granules can be used. In these compositions, theactive ingredient according to the invention is mixed with one or moreinert diluents or adjuvants, such as saccharose, lactose or starch.These compositions can comprise substances other than the diluents, forexample a lubricant such as magnesium stearate or a coating intended forcontrolled release.

As liquid compositions for oral administration, pharmaceuticallyacceptable solutions, suspensions, emulsions, syrups and elixirscontaining inert diluents such as water or paraffin oil can be used.These compositions can also comprise substances other than the diluents,for example wetting products, sweeteners or flavourings.

The compositions for parenteral administration can be sterile solutionsor emulsions. As solvent or vehicle, water, propylene glycol, apolyethylene glycol, vegetable oils, in particular olive oil, injectableorganic esters, for example ethyl oleate can be used. These compositionscan also contain adjuvants, in particular wetting agents, isotoningagents, emulsifiers, dispersants and stabilizers.

The sterilization can be carried out in several ways, for example usinga bacteriological filter, by irradiation or by heating. They can also beprepared in the form of sterile solid compositions which can bedissolved at the moment of use in sterile water or any other injectablesterile medium.

The compositions for topical administration can be for example creams,ointments, lotions or aerosols.

The compositions for rectal administration are suppositories or rectalcapsules, which, in addition to the active ingredient, containexcipients such as cocoa butter, semi-synthetic glycerides orpolyethylene glycols.

The compositions can also be aerosols. For use in the form of liquidaerosols, the compositions can be stable sterile solutions or solidcompositions dissolved at the moment of use in pyrogen-free sterilewater, in serum or any other pharmaceutically acceptable vehicle. Foruse in the form of dry aerosols intended to be directly inhaled, theactive ingredient is finely divided and combined with a diluent orhydrosoluble solid vehicle, for example dextran, mannitol or lactose.

In an advantageous embodiment, the present invention relates to apharmaceutical composition, said composition being in a formadministrable by at least one route selected from the group consistingof oral, intravenous, subcutaneous, nasal inhalatory, intramuscular,intraperitoneal and suppository, in particular oral or intravenousroute.

In an advantageous embodiment, the present invention relates to apharmaceutical composition, administrable by oral route at a dosecomprised from about 0.1 mg/kg to about 100 mg/kg of body weight.

In an advantageous embodiment, the present invention relates to apharmaceutical composition, under a form liable to be administrable byoral route, under the form of a unit dose comprised from 5 mg to 7500mg, in particular from 10 mg to 2000 mg, in particular from 50 to 1000mg.

Said pharmaceutical composition can be administered 1 to 4 times perday, preferably 2 or 3 times per day.

In an advantageous embodiment, the present invention relates to apharmaceutical composition, administrable by intravenous route at a dosecomprised from about 10 μg/kg to about 10 mg/kg.

In an advantageous embodiment, the present invention relates to apharmaceutical composition, under a form liable to be administrable byintravenous, under the form of a unit dose comprised from 0.1 mg to 1000mg, in particular from 10 mg to 1000 mg, in particular from 10 to 500mg, in particular from 10 to 100 mg.

Said pharmaceutical composition can be administered 1 to 4 times perday, preferably 2 or 3 times per day.

In another aspect, the present invention relates to a vaccinecomposition comprising, as active substance, a compound of formula (I-0)or (I-1), in particular (I-1a-1), (I-1a-2), (I-1a-3), (I-1a-4),(I-1b-1), (I-1b-2), (I-1b-3), (I-1b-4), (I-1c-1), (I-1c-2), (I-1c-3),(I-1c-4), (I-1c-5), (I-1c-6), (I-1c-7), (I-1c-8), (I-2a-1), (I-2a-2),(I-2a-3), (I-2a-4), (I-2b-1), (I-2b-2), (I-2b-3), (I-2b-4), (I-2c-1),(I-2c-2), (I-2c-3), (I-2c-4), (I-2c-5), (I-2c-6), (I-2c-7) or (I-2c-8),as described above, in association with a pharmaceutically acceptableadjuvant.

In another aspect, the present invention relates to a vaccinecomposition comprising, as active substance, a compound of formula (I)of one of the following formulae:

in association with a pharmaceutically acceptable adjuvant.

By “adjuvant” is meant any substance that enhances the immune responseto an antigen. Adjuvants useful in the vaccine composition according tothe present invention include mineral compounds including mineral saltssuch as calcium or aluminium salts, mineral or non-mineral oils,bacterial products, liposomes, saponins, iscoms and biodegradablemicroparticles. Well known adjuvants include Quil A, Marcol 52,Montanide 103 and pluronic polymers, such as L121 (BASF, N.J.).

The vaccine composition may include other adjuvants, including adjuvantsin liquid form. Such other adjuvants that may be used include squalene,Adjuvant 65 (containing peanut oil, mannide monooleate and aluminiummonostearate), surfactants such as hexadecylamine, octadecylamine,lysolecithin, dimethyl-dioctadecylammonium bromide,N,N-dioctradecyl-N,N¹-bis(2-hydroxyethyl)-propanediamine,methoxy-hexadecylglycerol and pluronic polyols, polyanions such aspyran, dextran sulfate, polyacrylic acid and carbopol, peptides andamino acids such as muramyl dipeptide, demethylglycine, tuftsin andtrehalose dimycolate, Adju-Phos, Algal Glucan, Algammulin, aluminiumsalts including aluminium hydroxide (Al(OH)₃), aluminium phosphate(A1PO₄), Alhydrogel, Antigen Formulation, Avridine, Bay R1005,Calcitriol, Calcium Phosphate, Calcium Phosphate Gel, Cholera Holotoxin(CT), Cholera Toxin B Subunit (CTB), CRL1005, DDA, DHEA, DMPC, DMPG,DOC/Alum Complex, Gamma Inulin, Gerbu Adjuvant, GMDP, Imiquimod,ImmTher, Interferon-gamma, Iscoprep 7.0.3, Loxoribine, LT-OA or LT OralAdjuvant, MF59, Mannan, MONTANIDE ISA 51, MONTANIDE ISA 720, MPL,MTP-PE, MTP-PE, Murametide, Murapalmitine, D-Murapalmitine, NAGO,Nonionic Surfactant Vesicles, Pleuran, PLGA, PGA and PLA, PMMA, PODDS,Poly Ra: Poly rU, Polyphosphazene, Polysorbate 80, Protein Cochleates,QS-21, Rehydragel HPA, Rehydragel LV, S-28463, SAF-1, Sclavo Peptide,Sendai Proteoliposomes, Sendai-Containing Lipid Matrices, Span 85,Specol, Stearyl Tyrosine, Theramide, Threonyl-MDP and Ty Particles.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising, in combination with a pharmaceuticallyacceptable vehicle:

-   -   at least one compound of formula (I-0) or (I-1), in particular        (I-1a-1), (I-1a-2), (I-1a-3), (I-1a-4), (I-1b-1), (I-1b-2),        (I-1b-3), (I-1b-4), (I-1c-1), (I-1c-2), (I-1c-3), (I-1c-4),        (I-1c-5), (I-1c-6), (I-1c-7), (I-1c-8), (I-2a-1), (I-2a-2),        (I-2a-3), (I-2a-4), (I-2b-1), (I-2b-2), (I-2b-3), (I-2b-4),        (I-2c-1), (I-2c-2), (I-2c-3), (I-2c-4), (I-2c-5), (I-2c-6),        (I-2c-7) or (I-2c-8), as defined above, and    -   at least one compound selected from the group consisting of        antibiotics, anti-inflammatory compounds, glucocorticoids,        immunosuppressive compounds and anti-TNF-alpha therapies,        said pharmaceutical composition being used for simultaneous or        separate use or use spread over time intended for the treatment        or the prevention of inflammatory bowel disease, in particular        Crohn disease or ulcerative colitis.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising, in combination with a pharmaceuticallyacceptable vehicle:

-   -   at least one compound of one of the following formulae:

and

-   -   at least one compound selected from the group consisting of        antibiotics, anti-inflammatory compounds, glucocorticoids,        immunosuppressive compounds and anti-TNF-alpha therapies,        said pharmaceutical composition being used for simultaneous or        separate use or use spread over time intended for the treatment        or the prevention of inflammatory bowel disease, in particular        Crohn disease or ulcerative colitis.

In another aspect, the present invention relates to a process ofpreparation of a compound of formula (I-1):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O or S;-   R₁ representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular isopropyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,        said (C₁-C₇)-alkyl, (C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl,        (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl,        (C₃-C₇)-heterocycloalkyl, (C₅-C₇)-heterocycloalkenyl,        CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl, CONH-(C₁-C₇)-alkyl, aryl,        alkyl aryl and CO-aryl being substituted or not by one or more        substituent(s), each independently selected from:    -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN,-   provided that when R₁ represents CHRa-NH₂, then Y can only represent    the following group (a):

-   comprising the following steps:-   when Y represents:

-   -   reaction between a compound of formula (1a):

-   -   wherein Rp represents an ad hoc hydroxyl protecting group, and a        compound of formula (2a):

-   -   in presence of triphenylphosphine, a coupling agent and        optionally 1-hydroxybenzotriazole (HOBt) or        1-hydroxy-7-aza-benzotriazole (HOAt),    -   to obtain a compound of formula (3a):

-   -   cleavage of the Rp protecting groups of said compound of formula        (3a), to obtain a compound of formula (I-1) wherein Y represents        (a), of following formula (I-1a):

-   when Y represents:

-   -   reaction between a compound of formula (1b):

-   -   and a compound of formula (2b):

-   -   to obtain a compound of formula (3b):

-   -   cleavage of the Rp protecting groups of said compound of formula        (3b), to obtain a compound of formula (I-1) wherein Y represents        (b), of following formula (I-1b):

-   when Y represents:

-   -   reaction between a compound of formula (1c):

-   -   and a compound of formula (2b):

-   -   to obtain a compound of formula (3b):

-   -   cleavage of the Rp protecting groups of said compound of formula        (3c), to obtain a compound of formula (I-1) wherein Y represents        (c), of following formula (I-1c):

In another aspect, the present invention relates to a process ofpreparation of a compound of formula (I-0):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O, S or NH;-   R representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular methyl, ethyl,        isopropyl or isobutyl,    -   a group of formula —(CH₂)_(i)—X′—(CH₂)_(j)H, wherein X′        represents O, S or NH, i is an integer from 1 to 7, and j is an        integer from 0 to 7, said group being in particular —CH₂—O—CH₃,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,    -   a cyclodextrin, said cyclodextrin being in particular chosen        from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD),        γ-cyclodextrin (γ-CD) and their derivatives, in particular        alkylated α-cyclodextrins, alkylated β-cyclodextrins and        alkylated γ-cyclodextrins, said cyclodextrin being more        particularly a β-cyclodextrin, even more particulary a        cyclodextrin of one of the following formulae:

said (C₁-C₇)-alkyl, group of formula —(CH₂)_(i)X′—(CH₂)_(j)—H,(C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl, (C₃-C₇)-cycloalkyl,(C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,(C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin beingsubstituted or not by one or more substituent(s), each independentlyselected from:

-   -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN,    -   SO₃H or one of its salts, in particular SO₃Na;

-   and its pharmaceutically acceptable salts,

-   provided that when R represents CHRa-NH₂, then Y can only represent    the following group (a):

with the proviso that said compound is not of one of the followingstructures:

and its salts,

-   comprising the following steps:-   when Y represents:

-   -   reaction between a compound of formula (1a):

-   -   wherein Rp represents an ad hoc hydroxyl protecting group,    -   and a compound of formula (2a):

wherein R₁ is a group R that is optionally protected by one or more adhoc protecting groups,

-   -   in presence of triphenylphosphine, a coupling agent and        optionally 1-hydroxybenzotriazole (HOBt) or        1-hydroxy-7-aza-benzotriazole (HOAt),    -   to obtain a compound of formula (3a):

-   -   cleavage of the Rp protecting groups and of the optional        protecting groups of R₁ in said compound of formula (3a), to        obtain a compound of formula (I-0) wherein Y represents (a), of        following formula (I-0a):

-   when Y represents:

-   -   reaction between a compound of formula (1b):

-   -   and a compound of formula (2b):

wherein R₁ is a group R that is optionally protected by one or more adhoc protecting groups,

-   -   to obtain a compound of formula (3b):

-   -   cleavage of the Rp protecting groups and of the optional        protecting groups of R₁ in said compound of formula (3b), to        obtain a compound of formula (I-0) wherein Y represents (b), of        following formula (I-0b):

-   when Y represents:

-   -   reaction between a compound of formula (1c):

-   -   and a compound of formula (2b):

wherein R₁ is a group R that is optionally protected by one or more adhoc protecting groups,

-   -   to obtain a compound of formula (3b):

-   -   cleavage of the Rp protecting groups and of the optional        protecting groups of R₁ in said compound of formula (3c), to        obtain a compound of formula (I-0) wherein Y represents (c), of        following formula (I-0c):

By “ad hoc hydroxyl protecting group” is meant a group intended toprotect an hydroxyl group against undesirable reactions during syntheticprocedures. Commonly used hydroxyl protecting groups are disclosed inGreene, “Protective Groups In Organic Synthesis” (John Wiley & Sons, NewYork (1981). Hydroxyl protecting groups comprise methoxymethyl,tetrahydropyranyl, t-butyl, allyl, benzyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, acetyl, pivaloyl and benzoyl groups, in particularacetyl group.

By “coupling agent” is meant a compound enabling the reaction between anamine containg compound and an acide containing compound to form anamide bond. Examples of suitable coupling agents are peptide couplingagents well known by the persons skilled in the art, in particulardicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU),O-(1-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU),O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP),(Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP), where the preferred agent is DIC.

The present invention also relates to a compound of the followingformula (I):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O or S;-   R representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular methyl, ethyl,        isopropyl or isobutyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,    -   a cyclodextrin, said cyclodextrin being in particular chosen        from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD),        γ-cyclodextrin (γ-CD) and their derivatives, in particular        alkylated α-cyclodextrins, alkylated β-cyclodextrins and        alkylated γ-cyclodextrins, said cyclodextrin being more        particularly a β-cyclodextrin, even more particulary a        β-cyclodextrin of the following formula:

said (C₁-C₇)-alkyl, (C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl,(C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,(C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin beingsubstituted or not by one or more substituent(s), each independentlyselected from:

-   -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN;

-   provided that when R represents CHRa-NH₂, then Y can only represent    the following group (a):

for use in the treatment or the prevention of pathologies belonging tothe group consisting of:

-   -   urinary tract infections, in particular painful bladder syndrome        and cystitis, more particularly interstitial cystitis, and    -   urinary tract infections in patients with a metabolic disease        correlated with enhanced apoptosis, in particular diabetes.

The present invention also relates to a compound of the followingformula (I):

wherein:

-   X represents NH, O, S or CH₂;-   n represents an integer being equal to 3, 4, 5, 6 or 7, n being in    particular equal to 5;-   Y represents a group selected from:

-   Z representing O, S or NH;-   R representing:    -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular methyl, ethyl,        isopropyl or isobutyl,    -   a group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H, wherein X′        represents O, S or NH, i is an integer from 1 to 7, and j is an        integer from 0 to 7, said group being in particular —CH₂—O—CH₃,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantyl,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,    -   a cyclodextrin, said cyclodextrin being in particular chosen        from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD),        γ-cyclodextrin (γ-CD) and their derivatives, in particular        alkylated α-cyclodextrins, alkylated β-cyclodextrins and        alkylated γ-cyclodextrins, said cyclodextrin being more        particularly a β-cyclodextrin, even more particulary a        cyclodextrin of one the following formulae:

said (C₁-C₇)-alkyl, group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H,(C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl, (C₃-C₇)-cycloalkyl,(C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,(C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin beingsubstituted or not by one or more substituent(s), each independentlyselected from:

-   -   a linear or branched (C₁-C₇)-alkyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, wherein the aryl is an aromatic or heteroaromatic group    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CHO,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   a halogen selected from the group comprising F, Cl, Br, and I,    -   CF₃,    -   OR_(a), wherein R_(a) represents:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NR_(b)R_(c), wherein R_(b) and R_(c) represent independently        from each other:        -   H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl,            CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is an aromatic or            heteroaromatic group,    -   NO₂,    -   CN,    -   SO₃H or one of its salts, in particular SO₃Na;

-   and its pharmaceutically acceptable salts,

-   provided that when R represents CHRa-NH₂, then Y can only represent    the following group (a):

with the proviso that said compound is not of the following structure:

for use in the treatment or the prevention of pathologies belonging tothe group consisting of:

-   -   urinary tract infections, in particular painful bladder syndrome        and cystitis, more particularly interstitial cystitis, and    -   urinary tract infections in patients with a metabolic disease        correlated with enhanced apoptosis, in particular diabetes.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-1), wherein R is R₁,R₁ representing:

-   -   H    -   a linear or branched (C₁-C₇)-alkyl, in particular isopropyl,    -   a linear or branched (C₂-C₇)-alkenyl,    -   a linear or branched (C₂-C₇)-alkynyl,    -   a (C₃-C₇)-cycloalkyl,    -   a (C₅-C₇)-cycloalkenyl,    -   a (C₃-C₇)-heterocycloalkyl,    -   a (C₅-C₇)-heterocycloalkenyl,    -   an aryl, said aryl being an aromatic or heteroaromatic group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group,    -   a CO-(C₁-C₇)-alkyl,    -   a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,    -   a CO₂H,    -   a CO₂-(C₁-C₇)-alkyl,    -   a CONH-(C₁-C₇)-alkyl,    -   CF₃,    -   adamantly,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid,

-   R₁ representing in particular:    -   a linear (C₁-C₇)-alkyl, more particularly methyl, ethyl, propyl        or butyl, optionally substituted by a —OH and/or a —NH₂ group,    -   a branched (C₃-C₇)-alkyl, more particularly isopropyl or        isobutyl,    -   a (C₃-C₇)-heterocycloalkyl, more particularly a pyrrolidine,    -   an aryl, said aryl being an aromatic or heteroaromatic group,        more particularly a phenyl, a pyridinyl, a pyrrole or an        imidazole, optionally substituted by a —OH, a —NH₂ or a —SO₃Na        group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group, more particulary a benzyl, a phenethyl or an ethyl        imidazolyl, optionally substituted by a —OH or a —NH₂ group,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid, in particular alanine, serine, proline,        phenylalanine, cysteine or histidine.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1), wherein Yrepresents:

of following formula (I-1a):

-   X, R₁ and n being as defined above,-   R₁ representing in particular a linear or branched (C₁-C₇)-alkyl,    more particularly isopropyl.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1), wherein Yrepresents:

of following formula (I-1b):

-   X, R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1), wherein Yrepresents:

of following formula (I-1c):

-   X, Z, R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I) is of particular formula (I-2), wherein R is R₂,R₂ representing a cyclodextrin, said cyclodextrin being in particularchosen from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin(γ-CD) and their derivatives, in particular alkylated α-cyclodextrins,alkylated β-cyclodextrins and alkylated γ-cyclodextrins, saidcyclodextrin being more particularly a β-cyclodextrin, even moreparticulary a β-cyclodextrin of the following formula:

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-2), wherein Yrepresents:

of following formula (I-2c):

-   X, R₂, n and Z being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1a-1):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1a-2):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1a-3):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1a-4):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1b-1):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1b-2):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1b-3):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1b-4):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-1):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-2):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-3):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-4):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-5):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-6):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-7):

-   R₁ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-1) is of following formula (I-1c-8):

-   R₁ and n being as defined above.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1a-1), (I-1a-2),(I-1a-3), (I-1a-4), (I-1b-1), (I-1b-2), (I-1b-3), (I-1b-4), (I-1c-1),(I-1c-2), (I-1c-3), (I-1c-4), (I-1c-5), (I-1c-6), (I-1c-7) or (I-1c-8),wherein R₁ represents:

-   -   a linear (C₁-C₇)-alkyl, more particularly methyl, ethyl, propyl        or butyl, optionally substituted by a —OH and/or a —NH₂ group,    -   a branched (C₃-C₇)-alkyl, more particularly isopropyl or        isobutyl,    -   a (C₃-C₇)-heterocycloalkyl, more particularly a pyrrolidine,    -   an aryl, said aryl being an aromatic or heteroaromatic group,        more particularly a phenyl, a pyridinyl, a pyrrole or an        imidazole, optionally substituted by a —OH, a —NH₂ or a —SO₃Na        group,    -   an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic        group, more particulary a benzyl, a phenethyl or an ethyl        imidazolyl, optionally substituted by a —OH or a —NH₂ group,    -   CHRa-NH₂, wherein Ra represents the side chain of a        proteinogenic aminoacid, in particular alanine, serine, proline,        phenylalanine, cysteine or histidine.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2a-1):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2a-2):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2a-3):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2a-4):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2b-1):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2b-2):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2b-3):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2b-4):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-1):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-2):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-3):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-4):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-5):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-6):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-7):

-   R₂ and n being as defined above.

In an advantageous embodiment of the use according to the invention, thecompound of formula (I-2) is of following formula (I-2c-8):

-   R₂ and n being as defined above.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I-1a-1), (I-1a-2),(I-1a-3), (I-1a-4), (I-1b-1), (I-1b-2), (I-1b-3), (I-1b-4), (I-1c-1),(I-1c-2), (I-1c-3), (I-1c-4), (I-1c-5), (I-1c-6), (I-1c-7), (I-1c-8),(I-2a-1), (I-2a-2), (I-2a-3), (I-2a-4), (I-2b-1), (I-2b-2), (I-2b-3),(I-2b-4), (I-2c-1), (I-2c-2), (I-2c-3), (I-2c-4), (I-2c-5), (I-2c-6),(I-2c-7) or (I-2c-8), wherein n is equal to 5.

In an advantageous embodiment, the present invention relates to the useaccording to the invention of a compound of formula (I) selected fromthe group consisting of:

and their salts, in particular their pharmaceutically acceptable salts.

DESCRIPTION OF THE DRAWINGS

FIG. 1 presents the adhesion levels of Adherent-Invasive E. coli strainLF82 to intestinal epithelial cells T84 in the presence of increasingdoses of compounds 5 and 10 or D-mannose, using co-, pre- andpost-incubation protocols (respectively FIGS. 1A, 1B and 1C). Resultsare expressed in percentages of residual adhesion, considering 100% asthe LF82 adhesion level in absence of any compound (means±sem). *:p<0.05; **:p<0.01; ***: p<0.001 (t test).

FIG. 2 presents the adhesion levels of Adherent-Invasive E. coli strainLF82 to colonic mucosa from CEABAC10 mice, in presence of compound 10 ata concentration of 100 μM. Infections were performed with 100 μL of abacterial suspension of AIEC LF82 at 2.5×10⁷ bacteria/mL. Results areexpressed in CFU/g of tissue, each point represents result for LF82adhesion in one colonic loop (horizontal bars=median).

FIG. 3 presents the body weight of CEABAC10 mice infected with 10⁹ AIECLF82 bacteria at day 0, after two oral administrations of the monovalentcompounds 5 and 10 at a dose of 10 mg/kg. Each point represents themean±sem of body weights for each group of mice. Results are expressedas percentages, day 0 (LF82 infection) being considered as 100%. NI:non-infected. a: p<0.001; b: p<0.01 compared to LF82-infected mice (ttest).

FIG. 4 presents the bacterial colonization in feces (FIGS. 4A, 4B and4C) and Disease Activity Index score (DAI) (D) at respectively day 1, 3and 4 post-infection of CEABAC10 mice infected with 10⁹ AIEC LF82 at day0. Two oral administrations of monovalent compounds 5 and 10 wererealized at a dose of 10 mg/kg. For FIGS. 4A to 4C, each pointrepresents the number of colony forming units (CFU) of AIEC LF82 pergram of feces for each mouse. Horizontal red bars represent medians.FIG. 4D presents DAI scores, expressed as means±sem. NI: non-infected.*: p<0.05; **: p<0.01; ***:p<0.001 (t test, in comparison with LF82group).

FIG. 5 presents the assessment of bacteria-associated to the ileum (FIG.5A) and to the colon (FIG. 5B) of CEABAC10 mice infected with AIEC LF82after oral treatment with monovalent compounds 5 and 10 (day 4post-infection). Mice were orally challenged with 10⁹ bacteria at day 0(DO) and monovalent compounds were administrated two times at a dose of10 mg/kg. Each point represents the number of colony forming units (CFU)of AIEC LF82 per gram of feces for each mouse, horizontal bars representmedians. NI: non-infected mice.

FIG. 6 presents the weight of spleens of AIEC LF82-infected CEABAC10mice after oral treatment with monovalent compounds 5 and 10 at day 4post-infection. Mice were orally challenged with 10⁹ bacteria at day 0(DO) and monovalent compounds were administrated two times at a dose of10 mg/kg. Results are expressed as means±sem. NI: non-infected. *:p<0.05 (t test).

FIG. 7 presents the contents in pro-inflammatory cytokines KC (FIG. 7A),TNF-α (FIG. 7B) and IL-23 (FIG. 7C) secreted by colonic mucosa at day 4post-infection of CEABAC10 mice infected with AIEC LF82 after oraltreatment with monovalent compounds 5 and 10. Mice were orallychallenged with 10⁹ bacteria at day 0 (DO) and monovalent compounds wereadministrated two times at a dose of 10 mg/kg. Each point represents thelevel of secreted cytokines in pg/mL, for one mouse. Horizontal barsrepresent medians. *: p<0.05 (t test).

FIG. 8 presents the residual adhesion of LF82 bacteria on T84 cells in apost-incubation assay. Results are expressed in percentage of residualconsidering 100% as adhesion of LF82 AIEC (infected control) without anyinhibitory compound (tested molecule). Different concentrations ofanti-FimH molecules are tested: 0.1, 1, 5, 10, 50 and 100 μM. Ttest=Student: a: p<0.05, b: p<0.01, c: p<0.001.

FIG. 9A presents the body weight of CEABAC10 transgenic mice uninfectedor infected with MEC LF82 measured at D=1, D=2, D=3 and D=4 days postinfection. Non-infected=Non infected mice (negative control); LF82=Infected mice with the LF82 AIEC strain (positive control); LF82+10,LF82+5=Infected mice with the LF82 AIEC strain treated with moleculestested at 10 mg/kg.

FIG. 9B presents the body weight of CEABAC10 transgenic mice uninfectedor infected with AlEC LF82 measured at D=1, D=2, D=3 and D=4 days postinfection. Non-infected =Non infected mice (negative control); LF82=Infected mice with the LF82 AIEC strain (positive control); LF82+16′,LF82+22′=Infected mice with the LF82 AIEC strain treated with moleculestested at 10 mg/kg.

FIG. 10 presents the DAI (Disease Activity Index) measured at D=3 dayspost infection. LF82=Infected mice with the LF82 AIEC strain (positivecontrol); LF82+16′, LF82+22′, LF82+10, LF82+5=Infected mice with theLF82 AIEC strain treated with molecules tested at 10 mg/kg.

FIG. 11 presents the colony forming units (CFU) measured per gram offeces at D=1 and D=3 days. NI=Non infected mice (negative control);LF82=Infected mice with the LF82 AIEC strain (positive control);LF82+16′, LF82+22′=Infected mice with the LF82 AIEC strain treated withmolecules tested at 10 mg/kg. Median value is indicated in horizontalline.

FIG. 12 presents the colony forming units (CFU) measured per gram ofileum and colon (mucosa) after D=3 days. LF82=Infected mice with theLF82 AIEC strain (positive control); LF82+16′, LF82+22′=Infected micewith the LF82 AIEC strain treated with molecules tested at 10 mg/kg.Median value is indicated in horizontal line.

FIG. 13 presents the Myelopexoridase activity (MPO) assessment inintestinal tissue from CEABAC10 mice measured in ng/mL. LF82=Infectedmice with the LF82 AIEC strain (positive control); LF82+10, LF82+5,LF82+16′, LF82+22′=Infected mice with the LF82 AIEC strain treated withmolecules tested at 10 mg/kg. Median value is indicated in horizontalline. T test=Student: *p<0.05, **P<0.01, ***p<0.001.

FIG. 14A presents the IL-23 assessment in blood from CEABAC10 micemeasured in pg/mL. Non-infected=non infected mice (negative control);LF82=Infected mice with the LF82 AIEC strain (positive control);LF82+10, LF82+5=Infected mice with the LF82 AIEC strain treated withmolecules tested at 10 mg/kg. Median value is indicated in horizontalline. T test=Student: *p<0.05, **P<0.01, ***p<0.001.

FIG. 14B presents the IL-23 assessment in blood from CEABAC10 micemeasured in pg/mL. Non-infected=non infected mice (negative control);LF82=Infected mice with the LF82 AIEC strain (positive control);LF82+16′, LF82+22′=Infected mice with the LF82 AIEC strain treated withmolecules tested at 10 mg/kg. Median value is indicated in horizontalline. T test=Student: *p<0.05, **P<0.01, ***p<0.001.

FIG. 15A presents the IL-1beta assessment in blood from CEABAC10 micemeasured in pg/mL. Non-infected=non infected mice (negative control);LF82=Infected mice with the LF82 AIEC strain (positive control);LF82+10, LF82+5=Infected mice with the LF82 AIEC strain treated withmolecules tested at 10 mg/kg. Median value is indicated in horizontalline. T test=Student: *p<0.05, **P<0.01, ***p<0.001

FIG. 15B presents the IL-1beta assessment in blood from CEABAC10 micemeasured in pg/mL. Non-infected=non infected mice (negative control);LF82=Infected mice with the LF82 AIEC strain (positive control);LF82+16′, LF82+DA22′=Infected mice with the LF82 AIEC strain treatedwith molecules tested at 10 mg/kg. Median value is indicated inhorizontal line. T test=Student: *p<0.05, **P<0.01, ***p<0.001.

EXAMPLES

A. Synthesis of monovalent heptylmannoside cyclodextrin compounds

Example 1 Synthesis of Compound 5

8-Oxaundec-10-ynyl 2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside 3

Mannosyl pentaacetate 1 (229 mg, 0.587 mmol), compound 2 (150 mg, 0.882mmol) and silver trifluoroacetate (194 mg, 0.878 mmol) were dissolved indry dichloromethane (3 mL). A solution of SnCl₄ 1M in dichloromethane(585 μL) was added and the mixture was stirred at rt for 3 h under argonatmosphere. The solution was diluted in dichloromethane (10 mL) andwashed with NaHCO₃ satd. (2×10 mL). The organic layer was dried,filtered and evaporated under reduced pressure. The residue waschromatographied on silica gel with ethyl acetate-cyclohexane (2-8) to(3-7) to afford 3 as a colorless oil (128 mg, 44%). Analytical data wereidentical as previously described [Gouin, S. G.; Wellens, A.; Bouckaert,J.; Kovensky, J. ChemMedChem. 2009, 5, 749-755].

8-Oxaundec-10-ynyl-α-D-mannopyranoside 4

3 (400 mg, 800 μmop was dissolved in MeOH (10 mL). A solution of freshlyprepared sodium methanolate 1M in methanol (500 μL) was added and themixture was stirred at rt for 4 h. Amberlyst IR120 (H⁺) was added andthe mixture stirred until pH reached 5. The resin was filtered off andthe solution was evaporated to dryness leading to unprotected product 4(263 mg, 99%).

[α]_(D)=+96 (c=0.2, MeOH); ¹H NMR (300 MHz, CD₃OD) δ=4.76 (1 H, d, J=1.6Hz, H-1), 4.14 (2 H, d, J=2.4 Hz, OCH₂C), 3.82-3.80 (2 H, m, H-2, H-3),3.75-3.69 (3 H, m, H-5, 2×H-6), 3.64 (1 H, t, J=9.3 Hz, H-4), 2.84 (1 H,t, CCH), 1.61-1.55 (4 H, br, 2×CH₂), 1.39 (6 H, br, 6×CH₂); ¹³C NMR (125MHz, D₂O): δ=102.4 (C1), 76.5 (CCH), 75.5, 73.5, 73.1, 71.8 (C-2,-3,-4,-5), 69.4 (CH₂O), 59.6 (CH₂CCH), 31.4, 31.3, 31.1, 28.1, 28.0(CH₂); HRMS (ES+): Found 355.1732 C₁₆H₂₈O₇Na requires 355.1733.

compound 5

Alkynyl-saccharide 4 (29 mg, 87 μmol) andmono-6-azido-6-deoxy-beta-cyclodextrin (50 mg, 43 μmol) were dissolvedin a DMF/H₂O mixture (2/0.5 mL). Copper sulfate (6.9 mg, 43 μmol) andsodium ascorbate (17 mg, 86 μmol) were added and the mixture was stirredat 70° C. for 30 minutes under μW irradiation. Ethylenediaminetetraacetic acid trisodium salt (50 mg, 127 μmol) was added and themixture was stirred for 10 minutes at rt. The mixture was evaporatedunder reduced pressure and the residue purified by preparative HPLCleading to compound 5 (33 mg, 51%) as a white powder afterlyophilisation.

[α]_(D)=+130 (c=0.1, MeOH); Tr=17 min; ¹H NMR (500 MHz, D₂O) δ=8.23 (1H, s, H_(triazol)), 5.51, 5.36, 5.30 (7 H, 3s, H-1^(I-VII)), 5.15 (1 H,s, H-1^(HM)), 4.20-3.20 (54 H, br, H-2,-3,-4,-5,^(I-VII),H-2,-3,-4,-5,-6^(HM), O-CH₂-triazol, 2×CH₂), 1.72, 1.65, 1.47 (10 H, br,(×CH₂), ¹³C NMR (125 MHz, D₂O): δ=146.1 (C=CH_(triazol)), 123.8(CH=C_(triazol)), 102.1, 101.8, 99.9 (C1^(I-VII), C1^(HM)), 83.1, 81.7,80.9, 80.3 (C4^(I-VII)), 72.1, 71.0, 70.4, 68.6, 67.0, 66.5, 63.0, 60.7,59.8, 58.8 (C2,-3,-4,-5,-6^(HM), CH₂O), 51.5 (C6^(I)), 29.1, 28.5, 28.0,25.7, 25.1 (CH₂); HRMS (ES+): Found 1514.5564 C₅₈H₉₇N₃O₄₁Na requires1514.5495.

B. Synthesis of mannosyl-O-heptylamides

a) Carboxylic acid, HOBt, DIC, PH₃P, THF, 0° C.→rt

General Procedure A: “One Pot” Staudinger-Amide Coupling:

The azide-functionalized carbohydrate (1 equiv.) and the carboxylic acid(1.8 equiv.) were combined with HOBt (1.8 equiv.) in a flask and driedfor more than 1 h in vacuo. This mixture was dissolved in dry THF (25mL/mmol azide) under nitrogen and cooled to 0° C. Then DIC (1.8 equiv.)was added and the solution was stirred for 10 min, followed by theaddition of Ph₃P (1.8 equiv.) and stirring for 1 h at 0° C. Then thereaction mixture was stirred overnight at room temperature, diluted withwater (50 mL) and extracted twice with ethyl acetate (30 mL). Thecombined organic phases were washed with brine, dried with MgSO₄ and themixture was filtered and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography.

Example 2 Compound 7

According to the general procedure A, mannosyl azide 6 (50 mg, 0.099mmol), isobutyric acid (16 mg, 0.178 mmol, 1.8 equiv.), HOBt (24 mg,0.178 mmol, 1.8 equiv.), DIC (28 μL, 0.178 mmol, 1.8 equiv.) and Ph₃P(47 mg, 0.178 mmol, 1.8 equiv.) were allowed to react in THF (2.5 mL).The crude product was purified by silica gel column chromatography(EtOAc/petroleum ether, 70:30→EtOAc as eluents) to give the amide 7 (42mg, 0.079 mmol, 80%) as an oil.

[α]_(D)=+71 (c=0.81 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): δ=1.12 (6H, d, J=6.9 Hz, 2×CH₃-isobutyricacid), 1.28-1.59 (10H, m), 1.97 (3H, s, AcO), 2.02 (3H, s, AcO), 2.08(3H, s, AcO), 2.13 (3H, s, AcO), 2.31 (1H, m, CH, isobutyric acid), 3.21(2H, m, H-7′), 3.41 (1H, m, H-1′a), 3.65 (1H, m, H-1′b), 3.95 (1H, ddd,J_(5,4)=9.5 Hz, J_(5,6b)=5.3 Hz, J_(5,6a)=2.5 Hz, H-5), 4.10 (1H, dd,J_(6a,6b)=12.2 Hz, J_(6a,5)=2.5 Hz, H-6a), 4.25 (1H, dd, J_(6b,6a)=12.2Hz, J_(6b,5)=5.3 Hz, H-6a), 4.77 (1H, d, J_(1,2)=1.7 Hz, H-1), 5.20 (1H,dd, J_(2,3)=3.3 Hz, J_(2,1)=1.7 Hz, H-2), 5.24 (1H, dd, J_(4,3)=10.1 Hz,J_(4,5)=9.6 Hz, H-4), 5.32 (1H, dd, J_(3,4)=10.1 Hz, J_(3,2)=3.3 Hz,H-3), 5.60 (1H, bs, NH).

¹³C NMR (100.6 MHz, CDCl₃): δ=19.6 (2×CH₃, isobutyric acid), 20.6(2×CH₃, 2×AcO), 20.7 (CH₃, AcO), 20.8 (CH₃, AcO), 25.8 (CH₂), 26.6(CH₂), 28.8 (CH₂), 29.0 (CH₂), 29.5 (CH₂), 35.6 (CH, isobutyric acid),39.2 (CH₂, C-7′), 62.5 (CH, C-6), 66.2 (CH), 68.3 (CH, CH₂, C-5, C-1′),69.1 (CH), 69.6 (CH, C-2), 97.5 (CH, C-1), 169.7 (C, AcO), 169.9 (C,AcO), 170.1 (C, AcO), 170.6 (C, AcO), 176.8 (C, amide).

MS (CI, NH₃): m/z 549 [M+NH₃]1⁺.

Example 3 Compound 8

According to the general procedure A, mannosyl azide 6 (50 mg, 0.099mmol), N-Boc-L-alanine (34 mg, 0.178 mmol, 1.8 equiv.), HOBt (24 mg,0.178 mmol, 1.8 equiv.), DIC (28 μL, 0.178 mmol, 1.8 equiv.) and Ph₃P(47 mg, 0.178 mmol, 1.8 equiv.) were allowed to react in THF (2.5 mL).The crude product was purified by silica gel column chromatography(EtOAc/petroleum ether, 70:30→EtOAc as eluents) to give the amide 8 (35mg, 0.055 mmol, 56%) as an oil.

[α]_(D)=+54 (c=0.92 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): δ=1.33 (3H, d, J=7.0 Hz, CH₃-alanine),1.25-1.76 (10H, m), 1.44 (3H, s, N-Boc), 2.00 (3H, s, AcO), 2.05 (3H, s,AcO), 2.10 (3H, s, AcO), 2.16 (3H, s, AcO), 3.24 (2H, t, J=6.6 Hz,H-7′), 3.43 (1H, m, H-1′a), 3.67 (1H, m, H-1′b), 3.97 (1H, ddd,J_(5,4)=8.2 Hz, J_(5,6b)=5.3 Hz, J_(5,6a)=2.5 Hz, H-5), 4.11 (1H, dd,J_(6a,6b)=12.1 Hz, J_(6a,5)=2.4 Hz, H-6a), 4.12 (1H, m , CH-alanine),4.28 (1H, dd, J_(6b,6a)=12.1 Hz, J_(6b,5)=5.3 Hz, H-6a), 4.79 (1H, d,J_(1,2)=1.6 Hz, H-1), 5.03 (1H, bs, NH), 5.22 (1H, dd, J_(2,3)=3.1 Hz,J_(2,1)=1.6 Hz, H-2), 5.27 (1H, dd, J_(4,3)=10.0 Hz, J_(4,5)=8.2 Hz,H-4), 5.34 (1H, dd, J_(3,4)=10.0 Hz, J_(3,2)=3.3 Hz, H-3), 6.19 (1H, bs,NH).

¹³C NMR(100.6 MHz, CDCl₃): δ=18.4 (CH₃, alanine), 20.7 (CH₃, AcO), 20.72(2 ×CH₃, AcO), 20.9 (CH₃, AcO), 25.8 (CH₂), 26.5 (CH₂), 28.3 (3 X CH₃,N-Boc), 28.8 (CH₂), 29.0 (CH₂), 29.3 (CH₂), 39.4 (CH₂, C-7′), 50.1 (C,N-Boc), 62.5 (CH, C-6), 66.2 (CH, C-1′), 68.4 (2 ×CH), 69.1 (CH), 69.7(CH, C-2), 97.5 (CH, C-1), 155.5 (C, amide), 169.7 (C, AcO), 170.0 (C,AcO), 170.1 (C, AcO), 170.6 (C, AcO), 172.4 (C, N-Boc).

MS (CI, NH3): m/z 633 [M]+

HRMS (MALDI, DHB): m/z calcd for C29H48N2O13Na [M+Na]+: 655.3049, found:655.3026.

Example 4 Compound 9

According to the general procedure A, mannosyl azide 6 (50 mg, 0.099mmol), picolinic acid (22 mg, 0.178 mmol, 1.8 equiv.), HOBt (24 mg,0.178 mmol, 1.8 equiv.), DIC (28 μL, 0.178 mmol, 1.8 equiv.) and Ph₃P(47 mg, 0.178 mmol, 1.8 equiv.) were allowed to react in THF (2.5 mL).The crude product was purified by silica gel column chromatography(EtOAc/petroleum ether, 70:30→EtOAc as eluents) to give the amide 9 (43mg, 0.076 mmol, 77%) as an oil.

[α]_(D)=+61 (c=1.03 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.30-1.69 (10H, m), 1.98 (3H, s, AcO), 2.03(3H, s, AcO), 2.09 (3H, s, AcO), 2.14 (3H, s, AcO), 3.39 (1H, m, H-1′a),3.46 (2H, q, J=6.8 Hz, H-7′), 3.66 (1H, m, H-1′b), 3.97 (1H, ddd,J_(5,4)=9.5 Hz, J_(5,6b)=5.2 Hz, J_(5,6a)=2.3 Hz, H-5), 4.09 (1H, dd,J_(6a,6b)=12.2 Hz, J_(6a,5)=2.3 Hz, H-6a), 4.28 (1H, dd, J_(6b,6a)=12.2Hz, J_(6b,5)=5.2 Hz, H-6a), 4.79 (1H, d, J_(1,2)=1.6 Hz, H-1), 5.22 (1H,dd, J_(2,3)=3.3 Hz, J_(2,1)=1.6 Hz, H-2), 5.26 (1H, dd, J_(4,3)=9.8 Hz,J_(4,5)=9.6 Hz, H-4), 5.34 (1H, dd, J_(3,4)=9.8 Hz, J_(3,2)=3.3 Hz,H-3), 7.41 (1H, ddd, J=7.6 Hz, J=4.8 Hz, J=1.3 Hz, picolinic), 7.84 (1H,ddd, J=7.6 Hz, J=7.6 Hz, J=1.7 Hz, picolinic), 8.08 (1H, bs, NH), 8.19(1H, bd, J=7.8 Hz, picolinic), 8.54 (1H, ddd, J=4.7 Hz, J=1.7 Hz, J=0.9Hz, picolinic).

¹³C NMR (100.6 MHz, CDCl₃): δ=20.7 (CH₃, AcO), 20.71 (2 X CH₃, AcO),20.9 (CH₃, AcO), 26.0 (CH₂), 26.8 (CH₂), 29.0 (CH₂), 29.1 (CH₂), 29.5(CH₂), 39.4 (CH₂, C-7′), 62.5 (CH, C-6), 66.2 (CH, C-1′), 68.3 (CH),68.4 (CH), 69.1 (CH), 69.7 (CH, C-2), 97.5 (CH, C-1), 122.3 (CH,picolinic acid), 126.1 (CH, picolinic acid), 137.5 (CH, picolinic acid),147.8 (CH, picolinic acid), 149.9 (C, picolinic acid), 164.0 (C, amide),169.7 (C, AcO), 169.9 (C, AcO), 170.1 (C, AcO), 170.6 (C, AcO).

MS (CI, NH3): m/z (%): 567 [M]+

HRMS (MALDI, DHB): m/z calcd for C27H38N2O11Na [M+Na]+: 598.2368, found:589.2374.

i. NaOMe, MeOH, rt, ii. Amberlite IR120 (H), iii. TFA-DCM, 0° C. vi. HClac. (for N-Boc protected compound 8).

General Procedure B: O-Acetyl Deprotection According to ZemplénConditions

The protected glycosyl amide (1 equiv.) was dissolved in dry MeOH (30mL) and sodium methoxide (1 M solution in MeOH, 10% per AcO) was added.The mixture was stirred for 4 h, neutralized with Amberlite IR120 (H),filtered and the solvents evaporated to dryness. The substrate wasdissolved in water and subjected to lyophilization.

General Procedure C: N-Boc Deprotection with Trifluoroacetic Acid

The Boc-protected amine was dissolved in DCM (2 mL/mmol) and TFA (2mL/mmol) was added at 0° C. The mixture was stirred for 1 h, evaporatedto dryness and co-evaporated with H₂O (3 times) and 0.5 N HCl (3 times).The substrate was dissolved in water and subjected to lyophilization.

Example 5 Compound 10

According to the general procedure B, using the amide 7 (81 mg, 0.128mmol) as starting material, the derivative 10 was obtained afterlyophilization (41 mg, 0.113 mmol, 93%), as an amorphous white solid.

[α]_(D)=+48.1 (c=1.32 in MeOD).

¹H NMR (300 MHz, MeOD): δ=1.10 (6H, d, J=6.9 Hz, 2×CH₃-isobutyric acid),1.29-1.64 (10H, m), 2.42 (1H, m, CH-isobutyric acid), 3.15 (2H, t, J=6.9Hz, C-7′), 3.41 (1H, m, H-1a′), 3.52 (1H, ddd, J_(5,4)=9.2 Hz,J_(5,6b)=5.6 Hz, J_(5,6a)=2.4 Hz, H-5), 3.61 (1H, dd, J_(4,3)=9.4 Hz,J_(4,5)=9.2 Hz, H-4), 3.67-3.75 (3H, m), 3.78 (1H, dd, J_(2,3)=3.3 Hz,J_(2,1)=1.7 Hz, H-2), 3.82 (1H, dd, J_(6b,6a)=11.9 Hz, J_(6b,5)=2.5 Hz,H-6b), 4.73 (1H, d, J_(1,2)=1.7 Hz, H-1).

¹³C NMR (100.6 MHz, MeOD): δ=20.0 (2×CH₃, 2×CH₃-isobutyric acid), 27.2(CH₂), 27.8 (CH₂), 30.1 (CH₂), 30.4 (CH₂), 30.5 (CH₂), 36.3 (CH,CH-isobutyric acid), 40.2 (CH₂, C-7′), 62.9 (CH, C-6), 68.5 (CH), 68.6(CH), 72.2 (CH, C-5), 72.6 (CH, C-1′), 74.6 (CH, C-2), 101.5 (CH, C-1),180.0 (C, amide).

MS (CI, NH₃): m/z 364 [M+H]⁺

Example 6 Compound 11

According to the general procedure B and C, using the amide 8 (81 mg,0.128 mmol) as starting material, the alanine derivative 11 was obtainedafter lyophilization (41 mg, 0.102 mmol, 80%), in form of ammoniumchloride salt, as an amorphous white solid.

[α]_(D)=+39.6 (c=1.21 in D₂O).

¹H NMR (300 MHz, D₂O): δ=1.12-1.48 (10H, m), 1.36 (3H, d, J=7.1 Hz,CH₃-alanine), 3.08 (2H, m, H-1′), 3.33-3.77 (8H, m), 3.87 (2H, q, J=7.1Hz, CH-alanine), 4.67 (1H, bs, H-1).

¹³C NMR(100.6 MHz, D₂O): δ=16.6 (CH₃, alanine), 24.9 (CH₂), 25.2 (CH₂),25.9 (CH₂), 28.0 (CH₂), 31.2 (CH₂), 39.5 (CH₂, C-7′), 60.9 (CH, C-6),61.8 (CH, C-1′), 66.8 (CH, alanine), 67.9 (CH, C-5), 70.1 (CH), 70.7(CH), 72.7 (CH, C-2), 99.7 (CH, C-1), 170.5 (C, amide).

HRMS (MALDI, DHB): m/z calcd for C₁₆H₃₂N₂O₇Na [M+Na]+: 387.2107, found:387.2119

Example 7 Compound 12

According to the general procedure B, using the amide 9 (25 mg, 0.048mmol) as starting material, the picolinic derivative 12 was obtainedafter lyophilization (19 mg, 0.048 mmol, quantitative) as an amorphouswhite solid.

[α]_(D)=+47.1 (c=1.81 in MeOH)

¹H NMR (300 MHz, MeOD): 1.34-1.68 (10H, m), 3.40 (1H, m, H-1′a), 3.42(2H, t, J=7.0 Hz, H-7′), 3.52 (1H, ddd, J_(5,4)=9.4 Hz, J_(5,6b)=5.4 Hz,J_(5,6a)=2.4 Hz, H-5), 3.62 (1H, dd, J_(4,3)=9.4 Hz, J_(4,5)=9.2 Hz,H-4), 3.68-3.76 (3H, m, H-3, H-6a, H-1′b), 3.78 (1H, dd, J_(2,3)=3.2 Hz,J_(2,1)=1.6 Hz, H-2), 3.82 (1H, dd, J_(6b,6a)=11.8 Hz, J_(6b,5)=2.4 Hz,H-6b), 4.73 (1H, d, J_(1,2)=1.6 Hz, H-1), 7.41 (1H, ddd, J=7.6 Hz, J=4.8Hz, J=1.3 Hz, picolinic), 7.53 (1H, ddd, J=7.6 Hz, J=4.8 Hz, J=1.3 Hz,picolinic), 7.95 (1H, ddd, J=7.7 Hz, J=7.7 Hz, J=1.7 Hz, picolinic),8.08 (1H, ddd, J=7.8 Hz, J=1.1 Hz, J=1.1 Hz, picolinic), 8.68 (1H, ddd,J=4.7 Hz, J=1.7 Hz, J=1.1 Hz, picolinic).

¹³C NMR(100.6 MHz, MeOD): δ=23.5 (CH₂), 27.3 (CH₂), 28.0 (CH₂), 30.2(CH₂), 30.5 (CH₂), 40.4 (CH₂, C-7′), 62.9 (CH, C-6), 68.5 (CH, C-1′),68.6 (CH), 72.2 (CH), 72.6 (CH), 74.5 (CH, C-2), 101.5 (CH, C-1), 123.0(CH, picolinic acid), 127.6 (CH, picolinic acid), 138.7 (CH, picolinicacid), 149.7 (CH, picolinic acid), 151.1 (C, picolinic acid), 166.6 (C,amide).

MS (CI, NH₃): m/z 399 [M+H]⁺

HRMS (MALDI, DHB): m/z calcd for C42H48O5 [M+Na]+: 421.1945, found:421.1965.

a) Carboxylic acid, HOBt, DIC, PH₃P, THF, 0° C.→rt

Example 8 Compound 1′:

According to the general procedure A, mannosyl azide 6 (100 mg, 0.205mmol), n-butyric acid (32 μL, 0.369 mmol, 1.8 equiv.), HOBt (50 mg,0.369 mmol, 1.8 equiv.), DIC (57 μL, 0.369 mmol, 1.8 equiv.) and Ph₃P(97 mg, 0.369 mmol, 1.8 equiv.) were allowed to react in DCM (5 mL). Thecrude product was purified by silica gel column chromatography(EtOAc/diethyl ether, 80:20 as eluents) to give the amide 1′ (47 mg,0.088 mmol, 43%) as an oil.

[α]_(D)=+37.5 (c=0.62 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): δ=0.94 (3H, t, J=7.4 Hz, CH₃-butyric acid),1.28-1.61 (10H, m), 1.66 (2H, m, CH₂-butyric acid), 1.99 (3H, s, AcO),2.04 (3H, s, AcO), 2.10 (3H, s, AcO), 2.14 (2H, m, CH₂-butyric acid),2.15 (3H, s, AcO), 3.24 (2H, m, H-7′), 3.44 (1H, m, H-1′a), 3.67 (1H, m,H-1′b), 3.97 (1H, ddd, J_(5,4)=9.5 Hz, J_(5,6b)=5.4 Hz, J_(5,6a)=2.5 Hz,H-5), 4.11 (1H, dd, J_(6a,6b)=12.3 Hz, J_(6a,5)=2.5 Hz, H-6a), 4.28 (1H,dd, J_(6b,6a)=12.3 Hz, J_(6b,5)=5.4 Hz, H-6a), 4.79 (1H, d, J_(1,2)=1.6Hz, H-1), 5.22 (1H, dd, J_(2,3)=3.2 Hz, J_(2,1)=1.7 Hz, H-2), 5.27 (1H,dd, J_(4,3)=10.1 Hz, J_(4,5)=9.6 Hz, H-4), 5.34 (1H, dd, J_(3,4)=10.1Hz, J_(3,2)=3.3 Hz, H-3), 5.55 (1H, bs, NH).

¹³C NMR (100.6 MHz, CDCl₃): δ=13.7 (CH₃, butyric acid), 19.1 (CH₂,butyric acid), 20.61 (2×CH₃, 2×AcO), 20.66 (CH₃, AcO), 20.8 (CH₃, AcO),25.8 (CH₂), 26.6 (CH₂), 28.8 (CH₂), 29.0 (CH₂), 29.4 (CH₂), 38.7 (CH₂,butyric acid), 39.3 (CH₂, C-7′), 62.4 (CH, C-6), 66.1 (CH), 68.3 (CH,CH₂, C-5, C-1′), 69.1 (CH), 69.6 (CH, C-2), 97.4 (CH, C-1), 169.7 (C,AcO), 169.9 (C, AcO), 170.1 (C, AcO), 170.6 (C, AcO), 172.9 (C, amide).

MS (CI, NH₃): m/z 532 [M+H]⁺

HRMS (ESI): m/z calcd for C₂₅H₄₁NO₁₁Na[M+Na]⁺: 554.2577, found:554.2571.

Example 9 Compound 2′

According to the general procedure A, mannosyl azide 6 (100 mg, 0.205mmol), O-acetylactic acid (81 mg, 0.615 mmol, 3 equiv.), HOBt (83 mg,0.615 mmol, 3 equiv.), DIC (95 μL, 0.615 mmol, 3 equiv.) and Ph₃P (97mg, 0.615 mmol, 3 equiv.) were allowed to react in DCM (5.1 mL). Thecrude product was purified by silica gel column chromatography(EtOAc/petroleum ether, 80:20→EtOAc as eluents) to give the amide 2′ (72mg, 0.125 mmol, 61%) as a colorless oil.

[α]_(D)=+53.9 (c=0.52 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): δ=1.26-1.34 (8H, m), 1.42 (3H, d, J=6.9 Hz,CH₃-lactic acid), 1.52 (2H, m), 1.95 (3H, s, AcO), 2.00 (3H, s, AcO),2.06 (3H, s, AcO), 2.10 (3H, s, AcO), 2.12 (3H, s, AcO), 3.23 (2H, q,J=6.7 Hz, H-7′), 3.40 (1H, m, H-1′a), 3.64 (1H, m, H-1′b), 3.93 (1H,ddd, J_(5,4)=9.3 Hz, J_(5,6b)=5.2 Hz, J_(5,6a)=2.3 Hz, H-5), 4.07 (1H,dd, J_(6a,6b)=12.3 Hz, J_(6a,5)=2.4 Hz, H-6a), 4.24 (1H, dd,J_(6b,6a)=12.3 Hz, J_(6b,5)=5.3 Hz, H-6a), 4.76 (1H, d, J_(1,2)=1.6 Hz,H-1), 5.13 (1H, q, J=6.7 Hz, CH-lactic acid), 5.18 (1H, dd, J_(2,3)=3.2Hz, J_(2,1)=1.6 Hz, H-2), 5.23 (1H, dd, J_(4,3)=10.0 Hz, J_(4,5)=9.3 Hz,H-4), 5.34 (1H, dd, J_(3,4)=10.0 Hz, J_(3,2)=3.3 Hz, H-3), 6.18 (1H, bs,NH).

¹³C NMR (100.6 MHz, CDCl₃): δ=17.8 (CH₃, CH₃-lactic acid), 20.61 (2×CH₃,2×AcO), 20.65 (CH₃, AcO), 20.8 (CH₃, AcO), 21.0 (CH₃, AcO), 25.8 (CH₂),26.5 (CH₂), 28.8 (CH₂), 29.0 (CH₂), 29.3 (CH₂), 39.1 (CH₂, C-7′), 62.4(CH₂, C-6), 66.1 (CH, C-5), 68.3 (CH, CH₂, C-3, C-1′), 69.1 (CH, C-4),69.6 (CH, C-2), 70.6 (CH, CH-lactic acid), 97.4 (CH, C-1), 169.4 (C,AcO), 169.7 (C, AcO), 169.9 (C, AcO), 170.0 (C, AcO), 170.2 (C, AcO),170.6 (C, amide).

MS (CI, NH₃): m/z 576 [M]⁺

HRMS (MALDI, DHB): m/z calcd for C₂₆H₄₁NO₁₃Na [M+Na ]⁺: 598.2470, found:598.2471.

i. NaOMe, MeOH, rt, ii. Amberlite IR120 (H).

Example 10 Compound 3′

According to the general procedure B, using the amide 1′ (47 mg, 0.088mmol) as starting material, the derivative 3′ was obtained afterlyophilization (31 mg, 0.085 mmol, 97%) as an amorphous white solid.

[α]_(D)=+59.3 (c=1.19 in MeOD).

¹H NMR (300 MHz, MeOD): δ=0.95 (3H, d, J=7.4 Hz, CH₃-butyric acid),1.30-1.70 (12H, m), 2.16 (2H, t, J=7.4 Hz, CH₂-butyric acid), 3.17 (2H,t, J=6.9 Hz, C-7′), 3.43 (1H, m, H-1a′), 3.53 (1H, ddd, J_(5,4)=9.3 Hz,J_(5,6b)=5.8 Hz, J_(5,6a)=2.4 Hz, H-5), 3.62 (1H, dd, J_(4,3)=9.5 Hz,J_(4,5)=9.2 Hz, H-4), 3.68-3.76 (3H, m, H-3, H-6a, 1′b), 3.79 (1H, dd,J_(2,3)=3.2 Hz, J_(2,1)=1.7 Hz, H-2), 3.82 (1H, dd, J_(6b,6a)=11.8 Hz,J_(6b,5)=2.3 Hz, H-6b), 4.73 (1H, bs, H-1).

¹³C NMR(100.6 MHz, MeOD): δ=13.96 (CH₃, CH₃-butyric acid), 20.0 (CH₃,CH₃-butyric acid), 27.2 (CH₂), 27.9 (CH₂), 30.1 (CH₂), 30.4 (CH₂), 30.5(CH₂), 39.0 (CH₂, CH₂-butyric acid), 40.3 (CH₂, C-7′), 62.9 (CH, C-6),68.5 (CH, C-1′), 68.6 (CH, C-4), 72.3 (CH, C-5), 72.6 (CH, C-3), 74.6(CH, C-2), 101.5 (CH, C-1), 176.5 (C, amide).

MS (CI, NH₃): m/z 364 [M+H]⁺

HRMS (MALDI, DHB): m/z calcd for C₁₇H₃₃N₁O₇Na [M+Na]⁺: 386.2149, found:386.2151

Example 11 Compound 4′

According to the general procedure B, using the amide 2′ (42 mg, 0.073mmol) as starting material, the butyric derivative 4′ was obtained afterlyophilization (28 mg, 0.069 mmol, 94%) as an amorphous white solid.

[α]_(D)=+20.7 (c=0.83 in MeOH).

¹H NMR (400 MHz, MeOD): δ=1.29-1.41 (8H, m), 1.33 (3H, d, J=6.8 Hz,CH₃-lactic acid), 1.53 (1H, m), 1.59 (1H, m), 3.21 (2H, t, J=7.1 Hz,H-7′), 3.42 (1H, m, H-1′a), 3.52 (1H, ddd, J_(5,4)=9.5 Hz, J_(5,6b)=5.7Hz, J_(5,6a)=2.3 Hz, H-5), 3.61 (1H, dd, J_(4,5)=9.5 Hz, J_(4,3)=9.5 Hz,H-4), 3.67-3.76 (3H, m, H-1′b, H-3, H-6a), 3.78 (1H, dd, J_(2,3)=3.2 Hz,J_(2,1)=1.8 Hz, H-2), 3.82 (1H, dd, J_(6b,6a)=11.8 Hz, J_(6b,5)=2.3 Hz,H-6b), 4.10 (1H, q, J=6.8 Hz, CH-lactic acid), 4.73 (1H, d, J_(1,2)=1.4Hz, H-1).

¹³C NMR(100.6 MHz, MeOD): δ=21.3 (CH₃, CH₃-lactic acid), 27.2 (CH₂),27.8 (CH₂), 30.1 (CH₂), 30.4 (CH₂), 30.5 (CH₂), 39.9 (CH₂, C-7′), 62.9(CH, C-6), 68.5 (CH, C-5), 68.7 (CH, C-1′), 69.1 (CH), 72.3 (CH), 72.7(CH, C-2), 74.5 (CH, CH-lactic acid), 101.5 (CH, C-1), 177.7 (C, amide).

MS (CI, NH₃): m/z 424 [M+NH₃]⁺

HRMS (ESI): m/z calcd for C₁₆H₃₁NO₈Na [M+Na]⁺: 388,4128, found: 388,4132

a) (R)-N-Boc-1-azidopropan-2-amine or 2-(azidomethy)pyridine, CuSO₄,VitC Na, 1,4-dioxane-H₂O, 50° C.

Example 12 Compound 5′

To a solution of mannosyl alkine 3 (100 mg, 0.200 mmol) and(R)-N-Boc-1-azidopropan-2-amine (60 mg, 0.300 mmol) in a mixture 3:1 of1,4-dioxane-H₂O (4 ml) were added CuSO₄ (6 mg, 0.040 mmol) and VitC Na(16 mg, 0.080 mmol) and the mixture was warmed up at 50° C. After 8 h,the mixture was concentrated and the crude was purified by silica gelcolumn chromatography (hexanes/AcOEt: 50/50→10/90 as eluents) to givethe triazol 5′ (128 mg, 0.183 mmol, 91%) as a colorless oil.

[α]_(D)=+63 (c=0.68 in CHCl₃)

¹H NMR (400 MHz, CDCl₃): 1.08 (3H, d, J=6.8 Hz, propylamine), 1.24-1.30(6H, m), 1.34 (9H, s, Boc), 1.52 (4H, m), 1.91 (3H, s, AcO), 1.96 (3H,s, AcO), 2.01 (3H, s, AcO), 2.07 (3H, s, AcO), 3.37 (1H, m, H-1′a), 3.44(2H, t, J=6.7 Hz, H-7′), 3.59 (1H, m, H-1′b), 3.90 (1H, ddd, J_(5,4)=9.7Hz, J_(5,6b)=5.4 Hz, J_(5,6a)=2.3 Hz, H-5), 3.99 (1H, m, propylamine),4.03 (1H, dd, J_(6a,6b)=12.3 Hz, J_(6a,5)=2.3 Hz, H-6a), 4.19 (1H, dd,J_(6b,6a)=12.3 Hz, J_(6b,5)=5.4 Hz, H-6a), 4.36 (2H, m,triazol-CH₂-propylamine), 4.53 (2H, bs O-CH₂-triazol), 4.72 (1H, d,J_(1,2)=1.6 Hz, H-1), 4.83 (1H, bs, NH), 5.15 (1H, dd, J_(2,3)=3.4 Hz,J_(2,1)=1.8 Hz, H-2), 5.19 (1H, dd, J_(4,3)=9.9 Hz, J_(4,5)=9.9 Hz,H-4), 5.32 (1H, dd, J_(3,4)=10.0 Hz, J_(3,2)=3.4 Hz, H-3), 7.50 (1H, bs,Triazol).

¹³C NMR (100.6 MHz, CDCl₃): δ=20.47 (2×CH₃, 2×AcO), 20.50 (CH₃, AcO),20.7 (CH₃, AcO), 25.8 (CH₃, propylamine), 28.1 (3×CH₃, N-Boc), 28.6-28.9(4×CH₂), 29.4 (CH₂), 62.5 (CH, C-6), 64.1 (CH₂, O-CH₂-triazol), 64.3(CH₂, triazol-CH_(2—) propylamine), 68.2 (CH, C-5), 68.3 (CH, C-1′),68.9 (CH, C-4), 69.5 (CH, C-2), 70.5 (CH, propylamine), 70.8 (CH₂,C-7′), 97.3 (CH, C-1), 123.1 (CH, triazol), 145.2 (C, triazol), 154.9(C, N-Boc), 169.5 (C, AcO), 169.7 (C, AcO), 169.9 (C, AcO), 170.4 (C,AcO).

MS (CI, NH₃): m/z 702 [M+H]⁺

HRMS (MALDI, DHB): m/z calcd for C₃₂H₅₂N₄O₁₃Na [M+Na]⁺: 723.3423, found:723.3430.

Example 13 Compound 6′

To a solution of mannosyl alkine 3 (100 mg, 0.200 mmol) and2-(azidomethy)pyridine (40 mg, 0.300 mmol) in a mixture of 3:1 of1,4-dioxane-H₂O (4 ml) were added CuSO₄ (6 mg, 0.040 mmol) and VitC Na(16 mg, 0.080 mmol) and the mixture was warmed up at 50° C. After 8 h,the mixture was concentrated and the crude was purified by silica gelcolumn chromatography (DCM→DCM/MeOH: 90/10 as eluents) to give thetriazol 6′ (120 mg, 0.191 mmol, 95%) as a colorless oil.

[α]_(D)=+51.2 (c=0.91 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.28-1.35 (8H, m), 1.57 (2H, m), 1.97 (3H, s,AcO), 2.02 (3H, s, AcO), 2.08 (3H, s, AcO), 2.13 (3H, s, AcO), 3.31 (1H,m, H-1′a), 3.49 (2H, t, J=6.7 Hz, H-7′), 3.64 (1H, m, H-1′b), 3.95 (1H,ddd, J_(5,4)=9.5 Hz, J_(5,6b)=5.3 Hz, J_(5,6a)=2.4 Hz, H-5), 4.08 (1H,dd, J_(6a,6b)=12.3 Hz, J_(6a,5)=2.3 Hz, H-6a), 4.26 (1H, dd,J_(6b,6a)=12.3 Hz, J_(6b,5)=5.3 Hz, H-6a), 4.59 (2H, s, O-CH₂-triazol),4.67 (1H, d, J_(1,2)=1.7 Hz, H-1), 5.21 (1H, dd, J_(2,3)=3.3 Hz,J_(2,1)=1.7 Hz, H-2), 5.25 (1H, dd, J_(4,3)=10.0 Hz, J_(4,5)=9.8 Hz,H-4), 5.32 (1H, dd, J_(3,4)=10.0 Hz, J_(3,2)=3.3 Hz, H-3), 5.68 (2H, s,triazol-CH₂-Py), 7.17 (1H, bd, J=7.8 Hz, Py), 7.25 (1H, ddd, J=7.6 Hz,J=4.9 Hz, J=1.1 Hz, Py), 7.67 (1H, ddd, J=7.8 Hz, J=7.8 Hz, J=1.8 Hz,Py), 7.68 (1H, bs, Triazol), 8.57 (1H, ddd, J=4.9 Hz, J=1.8 Hz, J=0.9Hz, Py).

¹³C NMR (100.6 MHz, CDCl₃): δ=20.65 (2×CH₃, 2×AcO), 20.68 (CH₃, AcO),20.9 (CH₃, AcO), 25.9-29.5 (5×CH₂), 55.6 (CH₂, triazol-CH₂-Py), 62.5(CH, C-6), 64.3 (CH₂, O-CH₂-triazol), 66.2 (CH, C-4), 68.3 (CH, C-5),68.4 (CH, C-1′), 69.1 (CH, C-3), 69.7 (CH, C-2), 70.8 (CH₂, C-7′), 97.5(CH₂, C-1), 122.4 (CH, Py), 122.9 (CH, triazol), 123.4 (CH, Py), 137.3(CH, Py), 145.8 (C, triazol), 149.7 (CH, Py), 154.4 (C, Py), 169.7 (C,AcO), 169.8 (C, AcO), 170.0 (C, AcO), 170.6 (C, AcO).

MS (CI, NH₃): m/z 635 [M]⁺

HRMS (MALDI, DHB): m/z calcd for C₃₀H₄₂N₄O₁₁Na [M+Na]⁺: 657.2742, found:657.2725.

i. NaOMe, MeOH, rt, ii. Amberlite IR120 (H), iii. TFA-DCM, 0° C. (forN-Boc protected 5′).

Example 14 Compound 7′

According to the general procedure B and C, using the triazol 5′ (253mg, 0.361 mmol) as starting material, the derivative 7′ was obtainedafter lyophilization (193 mg, 0.353 mmol, 98%), in form oftrifluoroacetate salt, as an amorphous white solid.

[α]_(D)=+61.3 (c=0.31 in MeOH)

¹H NMR (300 MHz, MeOD): 1.31-1.66 (13H, m), 3.43 (1H, m, H-1′a),3.49-3.98 (10H, m), 4.62 (2H, s, O-CH₂-triazol), 4.69 (2H, m,triazol-CH₂), 4.76 (1H, bs, H-1), 8.09 (1H, bs, Triazol).

¹³C NMR (100.6 MHz, MeOD): δ=16.36 (CH₃, propylamine), 27.1 (CH₂), 27.2(CH₂), 30.2 (CH₂), 30.4 (CH₂), 30.5 (CH₂), 53.4 (CH₂, O-CH₂-triazol),62.5 (CH, C-6), 64.5 (CH₂, triazol-CH₂-propylamine), 68.4 (CH), 68.6(CH₂, C-1′), 71.8 (CH), 72.2 (CH), 72.6(CH), 74.4 (CH₂, C-7′), 101.5(CH, C-1), 118.3 (C, q, J_(C,F)32 289.8 Hz, TFA), 126.2 (CH, triazol),146.6 (C, triazol), 163.1 (C, q, J_(C,F)=33.7 Hz, TFA).

MS (CI, NH₃): m/z 433 [M−TFA]⁺

Example 15 Compound 8′

According to the general procedure B, using the triazol 6′ (100 mg,0.157 mmol) as starting material, the pyridin derivative 8′ was obtainedafter lyophilization (72 mg, 0.154 mmol, 98%) as an amorphous whitesolid.

[α]_(D)=+36.3 (c=0.41 in MeOH)

¹H NMR (300 MHz, MeOD): 1.29-1.41 (6H, m), 1.53-1.62 (4H, m), 3.40 (1H,m, H-1′a), 3.50 (2H, t, J=6.6 Hz, H-7′), 3.54-3.75 (6H, m), 3.81 (1H,bd, J_(2,3)=3.8 Hz, H-2), 4.58 (2H, s, O-CH₂-triazol), 4.74 (1H, bs,H-1), 4.95 (2H, s, OH), 4.97 (1H, s, OH), 5.72 (2H, s, triazol-CH₂-Py),7.33 (1H, bd, J=8.0 Hz, Py), 7.38 (1H, dd, J=7.8 Hz, J=5.3 Hz, Py), 7.84(1H, ddd, J=7.8 Hz, J=7.8 Hz, J=1.5 Hz, Py), 8.06 (1H, bs, Triazol),8.54 (1H, bd, J=4.5 Hz, Py).

¹³C NMR(100.6 MHz, MeOD): δ=27.1 (CH₂), 27.3 (CH₂), 30.2 (CH₂), 30.5(CH₂), 30.6 (CH₂), 56.0 (CH₂, triazol-CH₂-Py), 62.7 (CH, C-6), 64.6(CH₂, O-CH₂-triazol), 68.5 (CH₂, C-1′), 68.6 (CH), 71.6 (CH₂, C-7′),72.3 (CH, C-2), 72.7 (CH), 74.5 (CH), 101.6 (CH, C-1), 123.9 (CH, Py),124.9 (CH, Py), 125.7 (CH, triazol), 139.2 (CH, Py), 146.5 (C, triazol),150.6 (CH, Py), 155.9 (C, Py).

MS (CI, NH₃): m/z 467 [M]⁺

HRMS (MALDI, DHB): m/z calcd for C₂₂H₃₄N₄O₇Na [M+Na]⁺: 489.2320, found:489.2314.

a) CuSO₄, VitC Na, DMF-H₂O, 70° C. b) i. NaOMe, MeOH, rt, ii. AmberliteIR120 (H).

Example 16 Compound 10′

Alkynyl-saccharide 4 (87 μmol) andmono-7-azido-7-deoxy-gamma-cyclodextrin (43 μmol) were dissolved in aDMF/H₂O mixture (2/0.5 mL). Copper sulfate (43 μmol) and sodiumascorbate (86 μmol) were added and the mixture was stirred at 70° C. for30 minutes under μW irradiation. Ethylenediamine tetraacetic acidtrisodium salt (127 μmol) was added and the mixture was stirred for 10minutes at rt. The mixture was evaporated under reduced pressure and theresidue purified by preparative HPLC leading to compound 10′ as a whitepowder after lyophilisation.

a) Pyridinmethyl propargyl ether, CuSO₄, VitC Na, 1,4-dioxane-H₂O, 50°C. b) NaOMe, MeOH.

Example 18 Compound 11′

To a solution of mannosyl azide 6 (100 mg, 0.205 mmol) and pyridinmethylpropargyl ether (36 mg, 0.246 mmol) in a mixture of 3:1 of1,4-dioxane-H₂O (4.1 ml) were added CuSO₄ (7 mg, 0.041 mmol) and VitC Na(16 mg, 0.082 mmol) and the mixture was warmed up at 65° C. After 8 h,the mixture was concentrated and the crude was purified by silica gelcolumn chromatography (AcOEt→AcOEt/MeOH: 90/10 as eluents) to give thetriazol 11′ (128 mg, 0.202 mmol, 98%) as a colorless oil.

[α]_(D)=+37.9 (c=0.83 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.29-1.41 (6H, m), 1.58 (2H, m), 1.91 (2H, m),1.99 (3H, s, AcO), 2.04 (3H, s, AcO), 2.09 (3H, s, AcO), 2.15 (3H, s,AcO), 3.42 (1H, m, H-1′a), 3.67 (1H, m, H-1′b), 3.96 (1H, ddd,J_(5,4)=9.3 Hz, J_(5,6b)=5.3 Hz, J_(5,6a)=2.4 Hz, H-5), 4.10 (1H, dd,J_(6a,6b)=12.3 Hz, J_(6a,5)=2.3 Hz, H-6a), 4.28 (1H, dd, J_(6b,6a)=12.3Hz, J_(6b,5)=5.3 Hz, H-6a), 4.35 (2H, t, J=7.3 Hz, H-7′), 4.72 (2H, s,O-CH₂-triazol), 4.77 (2H, s, O-CH₂-Py), 4.79 (1H, d, J_(1,2)=1.7 Hz,H-1), 5.22 (1H, dd, J_(2,3)=3.3 Hz, J_(2,1)=1.7 Hz, H-2), 5.27 (1H, dd,J_(4,3)=10.1 Hz, J_(4,5)=9.7 Hz, H-4), 5.34 (1H, dd, J_(3,4)=10.1 Hz,J_(3,2)=3.3 Hz, H-3), 7.19 (1H, dd, J=7.4 Hz, J=5.2 Hz, Py), 7.55 (1H,bd, J=7.8 Hz, Py), 7.59 (1H, bs, Triazol), 7.69 (1H, ddd, J=7.8 Hz,J=7.8 Hz, J=1.8 Hz, Py), 8.56 (1H, bd, J=4.8 Hz, Py).

¹³C NMR(100.6 MHz, CDCl₃): δ=20.73-20.88 (4×CH₃, 4×AcO), 25.9 (CH₂),26.7 (CH₂), 28.7 (CH₂), 29.1 (CH₂), 30.2 (CH₂), 50.3 (CH₂, C-7′), 62.5(CH, C-6), 64.4 (CH₂, O-CH₂-triazol), 66.2 (CH, C-4), 68.35 (CH, C-1′),68.40 (CH, C-5), 69.1 (CH, C-3), 69.7 (CH, C-2), 73.3 (CH₂, O-CH₂-Py),97.5 (CH₂, C-1), 121.7 (CH, Py), 122.4 (CH, Py),122.5 (CH, triazol),136.7 (CH, Py), 144.8 (C, triazol), 149.2 (CH, Py), 157.9 (C, Py), 169.7(C, AcO), 169.9 (C, AcO), 170.1 (C, AcO), 170.6 (C, AcO).

MS (MALDI): m/z 657 [M+Na]⁺

HRMS (MALDI, DHB): m/z calcd for C₃₀H₄₂N₄O₁₁[M]⁺: 635.2923, found:635.2944.

Example 19 Compound 12′

According to the general procedure B, using the triazol 11′ (110 mg,0.173 mmol) as starting material, the pyridin derivative 12′ wasobtained after lyophilization (7 mg, 0.154 mmol, 98%) as an amorphouswhite solid.

[α]_(D)=+51.2 (c=0.49 in MeOH)

¹H NMR (300 MHz, MeOD): 1.38 (6H, m), 1.58 (2H, m), 1.93 (2H, m), 1.99(3H, s, AcO), 3.41 (1H, m, H-1′a), 3.48-3.85 (7H, m), 4.43 (2H, t, J=7.1Hz, H-7′), 4.69 (2H, s, O-CH₂-triazol), 4.77 (3H, bs, O-CH₂-Py, H-1),7.37 (1H, dd, J=7.3 Hz, J=5.1 Hz, Py), 7.56 (1H, bd, J=7.9 Hz, Py), 7.86(1H, ddd, J=7.8 Hz, J=7.8 Hz, J=1.8 Hz, Py), 8.06 (1H, s, Triazol), 8.50(1H, bd, J=4.8 Hz, Py).

¹³C NMR(100.6 MHz, MeOD): δ=27.1 (CH₂), 27.3 (CH₂), 29.8 (CH₂), 30.4(CH₂), 31.2 (CH₂), 51.3 (CH₂, C-7′), 62.8 (CH, C-6), 64.7 (CH₂,O-CH₂-triazol), 68.4 (CH, C-1′), 68.6 (CH), 72.3 (CH), 72.7 (CH), 73.4(CH₂, O-CH₂-Py), 74.6 (CH), 101.5 (CH, C-1), 123.4 (CH, Py), 124.2 (CH,Py),125.2 (CH, Py), 138.9 (CH, triazol), 145.6 (C, triazol), 149.6 (CH,Py), 159.0 (C, Py).

MS (CI, NH₃): m/z 467 [M+H]⁺

C. Synthesis of Mannosyl-S-heptylamides

a) 7-bromo-l-heptanol, Et₂NH, DMF, rt. b) CCl₄, Ph₃P, DCM, 0° C.→rt. c)NaN₃, DMF, 70° C. d) Carboxylic acid, HOBt, DIC, PH₃P, THF, 0° C.→rt

Example 20 Compound 14

To a solution of acetylated 1-thiosugar 13 (1.28 g, 3.15 mmol) and7-bromo-1-heptanol (738 mg, 3.78 mmol, 1.2 equiv) in dry DMF (150 mL) atroom temperature under a nitrogen atmosphere, was added diethylamine(6.51 mL, 63.06 mmol, 20 equiv). After stirring for 8 hours,diethylamine and dimethylformamide were removed in vacuo. The crudeproduct was purified by silica gel column chromatography (Hexanes/EtOAc,50:50) to give the product 14 (1.42 g, 2.97 mmol, 94%) as an amorphouswhite solid.

[α]_(D)=+83.2 (c=1.13 in CHCl₃)

¹NMR (300 MHz, CDCl₃): 1.34 (6H, m), 1.62 (2H, m), 1.85 (2H, m), 1.99(3H, s, AcO), 2.05 (3H, s, AcO), 2.09 (3H, s, AcO), 2.16 (3H, s, AcO),2.61 (2H, m, H-1′), 3.40 (2H, t, J=6.8 Hz, H-7′), 4.08 (1H, dd,J_(6a,6b)=11.9 Hz, J_(6a,5)=1.9 Hz, H-6a), 4.32 (1H, dd, J_(6b,6a)=11.9Hz, J_(6b,5)=5.3 Hz, H-6a), 4.38 (1H, m, H-5), 5.25 (1H, d, J_(1,2)=1.4Hz, H-1), 5.24-5.35 (2H, m, H-3, H-4), 5.35 (1H, dd, J_(2,3)=2.8 Hz,J_(2,1)=1.4 Hz, H-2).

¹³C NMR (100.6 MHz, CDCl₃): δ=3.9 (CH3), 58.7 (CH3), 59.2 (CH3), 60.5(CH3), 60.8 (CH3), 66.2 (CH), 71.3 (CH2), 72.9 (CH), 73.4 (C), 79.4(CH), 81.0 (CH), 84.5 (CH).

MS (CI, NH₃): m/z: [M+NH₃]⁺496

HRMS (MALDI, DHB): m/z calcd for C₂₁H₃₄O₁₀SNa [M+Na]⁺: 501.1765, found:501.1785

Example 21 Compound 15

A solution of 14 (1.35 g, 2.82 mmol) and carbon tetrabromide (1.03 g,3.10 mmol) in dry DCM (15 mL), cooled to 0° C. was added Ph₃P (812 mg,3.10 mmol) in portions over 30 min with vigorous stirring. Upon additionof the phosphine, the colorless solution turned a pale brown color andwas stirred for an additional 2 h at room temperature. The mixture wasconcentrated and the crude was purified by silica gel columnchromatography (Hexanes/EtOAc, 80:20) to give the product 15 (1.41 g,2.61 mmol, 93%) as an amorphous white solid.

[α]_(D)=+83.8 (c=0.79 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.34 (6H, m), 1.62 (2H, m), 1.85 (2H, m), 1.99(3H, s, AcO), 2.05 (3H, s, AcO), 2.09 (3H, s, AcO), 2.16 (3H, s, AcO),2.61 (2H, m, H-1′), 3.40 (2H, t, J=6.8 Hz, H-7′), 4.08 (1H, dd,J_(6a,6b)=11.9 Hz, J_(6a,5)=1.9 Hz, H-6a), 4.32 (1H, dd, J_(6b,6a)=11.9Hz, J_(6b,5)=5.3 Hz, H-6a), 4.38 (1H, m, H-5), 5.25 (1H, d, J_(1,2)=1.4Hz, H-1), 5.24-5.35 (2H, m, H-3, H-4), 5.35 (1H, dd, J_(2,3)=2.8 Hz,J_(2,1)=1.4 Hz, H-2).

¹³C NMR(100.6 MHz, CDCl₃): δ=20.5 (CH₃, AcO), 20.6 (CH₃, AcO), 20.63(CH₃, AcO), 20.8 (CH₃, AcO), 27.9 (CH₂), 28.1 (CH₂), 28.4 (CH₂), 29.1(CH₂), 31.1 (CH₂, C-1′), 32.5 (CH₂), 33.7 (CH₂, C-7′), 62.3 (CH, C-6),66.2 (CH, C-3 or C-4), 68.8 (CH, C-5), 69.3 (CH, C-3 or C-4), 71.1 (CH,C-2), 82.4 (CH, C-1), 169.6 (C, AcO), 169.7 (C, AcO), 169.9 (C, AcO),170.5 (C, AcO).

MS (CI, NH₃): m/z: [M+NH₃]⁺560

HRMS (MALDI, DHB): m/z calcd for C₂₁H₃₃BrO₉SNa [M+Na]⁺: 563.0921, found:563.0932

Example 22 Compound 16

A solution of 15 (560 mg, 1.037 mmol) in DMF (10 mL) was added NaN₃ (135mg, 2.074 mmol) and the resulting mixture was stirred at 70° C.overnight. The mixture was diluted with Et₂O and washed with H₂O andbrine. The crude was purified by silica gel column chromatography(Hexanes/EtOAc, 70:30) to give the azide 16 (498 mg, 0.990 mmol, 96%) asa colorless oil.

[α]_(D)=+73.3 (c=0.67 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.25-1.65 (10H, m), 1.99 (3H, s, AcO), 2.05(3H, s, AcO), 2.09 (3H, s, AcO), 2.16 (3H, s, AcO), 2.60 (2H, m, H-1′),3.26 (2H, t, J=6.9 Hz, H-7′), 4.08 (1H, dd, J_(6a,6b)=11.9 Hz,J_(6a,5)=2.0 Hz, H-6a), 4.32 (1H, dd, J_(6b,6a)=11.9 Hz, J_(6b,5)=5.2Hz, H-6a), 4.38 (1H, m, H-5), 5.23-5.35 (3H, m, H-1, H-3, H-4), 5.33(1H, dd, J_(2,3)=2.9 Hz, J_(2,1)=1.5 Hz, H-2).

¹³C NMR(100.6 MHz, CDCl₃): δ=20.6 (CH₃, AcO), 20.7 (CH₃, AcO), 20.73(CH₃, AcO), 20.9 (CH₃, AcO), 26.5 (CH₂), 28.5 (CH₂), 28.6 (CH₂), 28.7(CH₂), 29.2 (CH₂), 31.2 (CH₂, C-1′), 51.3 (CH₂, C-7′), 62.4 (CH, C-6),66.2 (CH, C-3 or C-4), 68.9 (CH, C-5), 69.4 (CH, C-3 or C-4), 71.1 (CH,C-2), 82.4 (CH, C-1), 169.7 (C, AcO), 169.72 (C, AcO), 169.9 (C, AcO),170.5 (C, AcO).

MS (CI, NH₃): m/z: [M+NH₃]⁺521

HRMS (MALDI, DHB): m/z calcd for C₂₁H₃₃N₃O₉SNa [M+Na]⁺: 526.1830, found:526.1836

Example 23 Compound 17

According to the general procedure A, mannosyl azide 16 (50 mg, 0.096mmol), acetic acid (11 mg, 0.173 mmol, 1.8 equiv.), HOBt (23 mg, 0.173mmol, 1.8 equiv.), DIC (27 μL, 0.173 mmol, 1.8 equiv.) and Ph₃P (45 mg,0.173 mmol, 1.8 equiv.) were allowed to react in THF (2.4 mL). The crudeproduct was purified by silica gel column chromatography(EtOAc/petroleum ether, 70:30→EtOAc as eluents) to give the amide 17 (39mg, 0.075 mmol, 78%) as an oil.

[α]_(D)=+69.5 (c=0.81 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.27-1.65 (10H, m), 1.96 (3H, s, AcO), 1.98(3H, s, AcO), 2.04 (3H, s, AcO), 2.09 (3H, s, AcO), 2.15 (3H, s, AcO),2.59 (2H, m, H-1′), 3.21 (2H, q, J=6.8 Hz, H-7′), 4.08 (1H, dd,J_(6a,6b)=12.0 Hz, J_(6a,5)=2.1 Hz, H-6a), 4.30 (1H, dd, J_(6b,6a)=12.0Hz, J_(6b,5)=5.1 Hz, H-6a), 4.36 (1H, m, H-5), 5.22-5.34 (3H, m, H-1,H-3, H-4), 5.32 (1H, dd, J_(2,3)=3.0 Hz, J_(2,1)=1.6 Hz, H-2), 5.57 (1H,bs, NH).

¹³C NMR(100.6 MHz, CDCl₃): δ=20.6 (CH₃, AcO), 20.70 (CH₃, AcO), 20.75(CH₃, AcO), 20.9 (CH₃, AcO), 23.3 (CH₃, acetamide), 26.7 (CH₂), 28.5(CH₂), 28.7 (CH₂), 29.1 (CH₂), 29.5 (CH₂), 31.2 (CH₂, C-1′), 39.5 (CH₂,C-7′), 62.4 (CH, C-6), 66.2 (CH, C-3 or C-4), 68.9 (CH, C-5), 69.4 (CH,C-3 or C-4), 71.2 (CH, C-2), 82.4 (CH, C-1), 169.7 (C, acetamide), 169.8(C, AcO), 169.96 (C, AcO), 169.99 (C, AcO), 170.6 (C, AcO).

MS (CI, NH₃): m/z: [M]⁺ 520

HRMS (MALDI, DHB): m/z calcd for C₂₇H₃₈N₂O₁₀SNa [M+Na]⁺: 542.2036,found: 542.2028

Example 24 Compound 18

According to the general procedure A, mannosyl azide 16 (150 mg, 0.289mmol), N-Boc-L-alanine (98 mg, 0.520 mmol, 1.8 equiv.), HOBt (70 mg,0.520 mmol, 1.8 equiv.), DIC (80 μL, 0.520 mmol, 1.8 equiv.) and Ph₃P(136 mg, 0.520 mmol, 1.8 equiv.) were allowed to react in THF (27.3 mL).The crude product was purified by silica gel column chromatography(EtOAc/petroleum ether, 50:50→EtOAc as eluents) to give the amide 18 (97mg, 0.149 mmol, 52%) as an oil.

[α]_(D)=+39.9 (c=1.27 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): δ=1.11-1.63 (10H, m),1.34 (3H, d, J=7.1 Hz,CH₃-alanine), 1.42 (9H, s, N-Boc), 1.98 (3H, s, AcO), 2.04 (3H, s, AcO),2.07 (3H, s, AcO), 2.15 (3H, s, AcO), 2.53 (2H, m, H-1′), 2.99 (2H, m,H-7′), 4.04-4.38 (4H, m, H-5, H-6a, H-6b, CH-alanine), 4.21-4.29 (3H, m,H-1, H-3, H-4), 5.32 (1H, dd, J_(2,3)=3.0 Hz, J₂=1.7 Hz, H-2), 5.36 (1H,bs, NH), 5.66 (1H, bs, NH).

¹³C NMR(100.6 MHz, CDCl₃): δ=20.5 (CH₃, AcO), 20.60 (CH₃, AcO), 20.63(CH₃, AcO), 20.8 (CH₃, AcO), 26.5 (CH₃, alanine), 28.2 (3 X CH₃, N-Boc),28.5 (CH₂), 28.6 (CH₂), 29.1 (CH₂), 29.3 (CH₂), 30.2 (C, N-Boc), 31.1(CH₂), 39.3 (CH₂, C-7′), 41.8 (CH₂, C-1′), 62.3 (CH, C-6), 68.8 (CH),69.4 (CH), 71.1 (CH, C-2), 82.4 (CH, C-1), 157.1 (C, amide), 169.6 (C,AcO), 169.7 (C, AcO), 169.9 (C, AcO), 170.5 (C, AcO), 172.5 (C, N-Boc).

MS (CI, NH₃): m/z: [M]⁺649

HRMS (MALDI, DHB): m/z calcd for C₂₉H₄₈N₂O₁₂SNa [M+Na]⁺: 671.2820,found: 671.2803

Example 25 Compound 19

According to the general procedure A, mannosyl azide 16 (100 mg, 0.193mmol), picolinic acid (43 mg, 0.347 mmol, 1.8 equiv.), HOBt (47 mg,0.347 mmol, 1.8 equiv.), DIC (54 μL, 0.347 mmol, 1.8 equiv.) and Ph₃P(91 mg, 0.347 mmol, 1.8 equiv.) were allowed to react in DMF (5 mL). Thecrude product was purified by silica gel column chromatography(DCM→DCM/MeOH, 90:10 as eluents) to give the amide 19 (83 mg, 0.142mmol, 74%) as an oil.

[α]_(D)=+55.7 (c=1.01 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.36-1.68 (10H, m), 1.98 (3H, s, AcO), 2.04(3H, s, AcO), 2.09 (3H, s, AcO), 2.16 (3H, s, AcO), 2.60 (2H, m, H-1′),3.46 (2H, q, J=6.8 Hz, H-7′), 4.08 (1H, dd, J_(6a,6b)=11.9 Hz,J_(6a,5)=1.9 Hz, H-6a), 4.31 (1H, dd, J_(6b,6a)=11.9 Hz, J_(6b,5)=5.2Hz, H-6a), 4.37 (1H, m, H-5), 5.23-5.30 (3H, m, H-1, H-3, H-4), 5.33(1H, dd, J_(2,3)=2.8 Hz, J_(2,1)=1.6 Hz, H-2), 7.41 (1H, ddd, J=7.7 Hz,J=4.9 Hz, J=1.3 Hz, picolinic), 7.84 (1H, ddd, J=7.6 Hz, J=7.6 Hz, J=1.7Hz, picolinic), 8.05 (1H, bs, NH), 8.19 (1H, bd, J=7.8 Hz, picolinic),8.54 (1H, ddd, J=4.7 Hz, J=1.7 Hz, J=0.9 Hz, picolinic).

¹³C NMR (100.6 MHz, CDCl₃): δ=20.53 (CH₃, AcO), 20.60 (CH₃, AcO), 20.63(CH₃, AcO), 20.8 (CH₃, AcO), 26.7 (CH₂), 28.5 (CH₂), 28.7 (CH₂), 29.2(CH₂), 29.5 (CH₂), 31.1 (CH₂, C-1′), 39.2 (CH₂, C-7′), 62.3 (CH, C-6),66.2 (CH, C-3 or C-4), 68.8 (CH, C-5), 69.4 (CH, C-3 or C-4), 71.1 (CH,C-2), 82.4 (CH, C-1), 122.1 (CH, picolinic acid), 126.0 (CH, picolinicacid), 137.2 (CH, picolinic acid), 147.9 (CH, picolinic acid), 149.9 (C,picolinic acid), 164.1 (C, amide), 169.6 (C, AcO), 169.7 (C, AcO), 169.9(C, AcO), 170.5 (C, AcO).

MS (CI, NH₃): m/z: [M+NH₃]⁺ 583

HRMS (MALDI, DHB): m/z calcd for C₂₇H₃₈N₂O₁₀SNa [M+Na]⁺: 605.2139,found: 605.2129

i. NaOMe, MeOH, rt, ii. Amberlite IR120 (H), iii. TFA-DCM, 0° C. vi. HClac. (for N-Boc protected compound 18).

Example 26 Compound 20

According to the general procedure B, using the amide 17 (20 mg, 0.038mmol) as starting material, the derivative 20 was obtained afterlyophilization (17 mg, 0.037 mmol, 98%) as an amorphous white solid.

[a]_(D)=+53.9 (c=0.69 in MeOD).

¹H NMR (300 MHz, MeOD): δ=1.29-1.71 (10H, m), 1.92 (3H, s, acetamide),2.64 (2H, m, H-7′), 3.15 (2H, t, J=6.9 Hz, H-1′), 3.64-3.92 (6H, m),5.21 (1H, d, J₁ ₂=1.3 Hz, H-1).

¹³C NMR (100.6 MHz, MeOD): δ=22.5 (CH₃, acetamide), 27.8 (CH₂), 29.7(CH₂), 29.9 (CH₂), 30.3 (CH₂), 30.6 (CH₂), 31.8 (CH₂, C-1′), 40.5 (CH₂,C-7′), 62.7 (CH, C-6), 68.9 (CH), 73.1 (CH), 73.8 (CH, C-5), 74.9 (CH,C-2), 86.4 (CH, C-1), 173.2 (C, acetamide).

MS (CI, NH₃): m/z 352 [M+H]⁺

HRMS (ESI): m/z calcd for C₁₅H₂₉O₆NSNa [M+Na]⁺: 374.1613, found:374.1615

Example 27 Compound 21

According to the general procedure B and C, using the amide 18 (51 mg,0.078 mmol) as starting material, the alanine derivative 21 was obtainedafter lyophilization (31 mg, 0.074 mmol, 95%), in form of ammoniumchloride salt, as an amorphous white solid.

[a]_(D)=+61.3 (c=0.61 in D₂O).

¹H NMR (300 MHz, D₂O): δ=1.12-1.48 (10H, m), 1.36 (3H, d, J=7.1 Hz,CH₃-alanine), 2.63 (2H, m, H-7′), 3.42 (2H, m, H-1′), 3.31-3.87 (7H, m),4.64 (1H, bs, H-1).

¹³C NMR(100.6 MHz, D₂O): δ=16.6 (CH₃, alanine), 24.9 (CH₂), 25.2 (CH₂),25.9 (CH₂), 28.0 (CH₂), 31.2 (CH₂), 61.8 (CH, C-1′), 39.5 (CH₂, C-7′),60.9 (CH, C-6), 66.8 (CH, alanine), 67.9 (CH), 70.1 (CH), 70.7 (CH),72.7 (CH, C-2), 85.9 (CH, C-1), 170.5 (C, amide).

MS (CI, NH₃): m/z 417 [M]⁺

HRMS (ESI): m/z calcd

Example 28 Compound 22

According to the general procedure B, using the amide 19 (32 mg, 0.055mmol) as starting material, the derivative 22 was obtained afterlyophilization (22 mg, 0.053 mmol, 96%) as an amorphous white solid.

[α]_(D)=+53.9 (c=0.69 in MeOD).

¹H NMR (300 MHz, MeOD): δ=1.28-1.69 (10H, m), 2.63 (2H, m, H-7′), 3.42(2H, m, H-1′), 3.64-3.93 (6H, m), 5.21 (1H, d, J_(1,2)=1.0 Hz, H-1),7.41 (1H, ddd, J=7.6 Hz, J=4.8 Hz, J=1.3 Hz, picolinic), 7.53 (1H, ddd,J=7.6 Hz, J=4.8 Hz, J=1.3 Hz, picolinic), 7.95 (1H, ddd, J=7.7 Hz, J=7.7Hz, J=1.7 Hz, picolinic), 8.09 (1H, ddd, J=7.8 Hz, J=1.1 Hz, J=1.1 Hz,picolinic), 8.62 (1H, ddd, J=4.7 Hz, J=1.7 Hz, J=1.1 Hz, picolinic).

¹³C NMR(100.6 MHz, MeOD): δ=27.9 (CH₂), 29.7 (CH₂), 29.9 (CH₂), 30.5(CH₂), 30.6 (CH₂), 31.8 (CH₂, C-1′), 40.4 (CH₂, C-7′), 62.7 (CH, C-6),68.9 (CH), 73.2 (CH), 73.8 (CH, C-5), 74.9 (CH, C-2), 86.4 (CH, C-1),123.0 (CH, picolinic), 127.6 (CH, picolinic), 138.8 (CH, picolinic),149.8 (CH, picolinic), 151.1 (C, picolinic), 166.6 (C, amide).

MS (CI, NH₃): m/z 415 [M+H]⁺

HRMS (ESI): m/z calcd for C₁₉H₃₀N₂O₆SNa [M+Na]⁺: 437.1722, found:437.1735

a) CBr₄, Ph₃P, DCM, 0° C.→rt. b) 1-bromo-7-propargyloxyheptane (13′),Et₂NH, DMF, rt. c) CuSO₄, VitC Na, DMF-H₂O, 70° C. d) CuSO₄, VitC Na,DMF-H₂O, 70° C.

Example 29 Compound 13′

A solution of 7-O-propargylheptanediol (500 mg, 2.941 mmol) and carbontetrabromide (1.07 g, 3.235 mmol) in dry DCM (15 mL), cooled to 0° C.was added Ph₃P (848 mg, 3.235 mmol) in portions over 30 min withvigorous stirring. Upon addition of the phosphine, the colorlesssolution turned a pale brown color and was stirred for an additional 3 hat room temperature. The mixture was concentrated and the crude waspurified by silica gel column chromatography (Hexanes/EtOAc, 70:30) togive the product 13′ (625 mg, 2.682 mmol, 91%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ=1.30-1.48 (6H, m), 1.59 (2H, m), 1.86 (2H,m), 2.41 (1H, t, J=2.4 Hz, CH-propargyl), 3.40 (2H, t, J=6.8 Hz), 3.51(2H, t, J=6.5 Hz), 4.13 (2H, d, J=2.4 Hz, CH₂-propargyl).

¹³C NMR(100.6 MHz, CDCl₃): δ=25.9 (CH₂), 28.1 (CH₂), 28.5 (CH₂), 29.4(CH₂), 32.7 (CH₂), 33.9 (CH₂), 58.0 (CH₂, CH₂-propargyl), 70.1 (CH₂),74.1 (CH, CH-propargyl), 77.2 (C, C-propargyl).

Example 30 Compound 14′

To a solution of acetylated 1-thiosugar 13 (944 mg, 2.325 mmol) and1-bromo-7-propargyloxyheptane 13′ (650 mg, 2.789 mmol, 1.2 equiv) in DMF(93 mL) at rt under a nitrogen atmosphere, was added diethylamine (4.8mL, 46.500 mmol, 20 equiv). After stirring for 8 hours, diethylamine andDMF were removed in vacuo. The crude product was purified by silica gelcolumn chromatography (Hexanes/EtOAc, 80:20) to give the product 14′(1026 mg, 1.984 mmol, 85%) as a colorless oil.

[α]_(D)=+47.2 (c=0.28 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.18-1.36 (8H, m), 1.53 (2H, m), 1.99 (3H, s,AcO), 2.05 (3H, s, AcO), 2.10 (3H, s, AcO), 2.16 (3H, s, AcO), 2.42 (1H,t, J=2.4 Hz, propargyl), 2.60 (2H, m, H-1′), 3.50 (2H, t, J=3.5 Hz,H-7′), 4.08 (1H, dd, J_(6a,6b)=11.9 Hz, J_(6a,5)=2.0 Hz, H-6a), 4.13(2H, d, J=2.4 Hz, propargyl), 4.32 (1H, dd, J_(6b,6a)=11.9 Hz,J_(6b,5)=5.3 Hz, H-6b), 4.38 (1H, m, H-5), 5.25 (1H, d, J_(1,2)=1.4 Hz,H-1), 5.27-5.34 (3H, m, H-2, H-3, H-4).

¹³C NMR(100.6 MHz, CDCl₃): δ=20.4 (CH₃, AcO), 20.47 (CH₃, AcO), 20.50(CH₃, AcO), 20.7 (CH₃, AcO), 25.74 (CH₂), 28.5 (CH₂), 28.6 (CH₂), 29.1(CH₂), 29.2 (CH2), 31.1 (C-1′, CH₂), 31.5 (CH₂), 57.8 (CH₂,CH₂-propargyl), 62.2 (CH₂, C-6), 66.1 (CH, C-3 or C-4), 68.7 (CH, C-5),69.2 (CH, C-3 or C-4), 69.8 (CH₂, C-7′), 70.9 (CH, C-2), 73.9 (CH,CH-propargyl), 79.8 (C, C-propargyl), 82.3 (CH, C-1), 169.5 (C, AcO),169.5 (C, AcO), 169.7 (C, AcO), 170.3 (C, AcO).

MS (CI, NH₃): m/z: [M+NH₃]⁺534

HRMS (MALDI, DHB): m/z calcd for C₂₄H₃₆O₁₀S [M+Na]⁺: 539.1921, found:539.1945.

Example 31 Compound 15′

To a solution of 6′-azido-2,3,6-O-acetyl-β-Cyclodextrin (150 mg, 0.075mmol) and alkyne 14′ (47 mg, 0.090 mmol) in a mixture DMF-H₂O (3:1, 3.8ml) were added CuSO₄ (2 mg, 0.015 mmol) and VitC Na (6 mg, 0.030 mmol)and the mixture was warmed up at 60° C. After 12 h, the mixture wasdiluted with water, extracted with AcOEt, dried, concentrated and thecrude was purified by silica gel column chromatography(AcOEt→AcOEt/MeOH: 95/5 as eluents) to give the monovalent derivative15′ (128 mg, 0.051 mmol, 68%) as a colorless solid.

[α]_(D)=+101.7 (c=0.21 in CHCl₃)

¹H NMR (400 MHz, CDCl₃) δ=1.22-1.44 (6H, m), 1.60 (4H, m), 1.97-2.15(78H, m, 26×AcO), 2.59 (2H, m, H-1′), 3.50 (2H, t, J=6.7 Hz, H-7′),3.54-3.78 (8H, m), 4.03-4.70 (18H, m), 4.72-4.86 (6H, m, 6×H-2 CD), 4.94(1H, dd, J=8.4 Hz, J=3.6 Hz, H-2 CD), 5.00-5.13 (6H, m, 6×H-1 CD),5.15-5.38 (12H, m), 5.64 (1H, d, J=3.9 Hz, H-1 CD), 7.59 (1H, s,triazol).

¹³C NMR (125 MHz, CDCl₃): δ=20.3-20.7 (24×CH₃, AcO), 25.8 (CH₂), 28.8(CH₂), 29.9 (CH₂), 29.3 (CH₂), 29.4 (CH₂), 31.2 (CH₂, C-1′thioglycoside), 50.4 (CH₂, C-6 CD), 59.5-82.9 (9CH₂, 32CH), 82.6 (CH,C-1 thioglycoside), 96.0-96.6 (7×CH, C-1 CD), 125.5 (CH, triazol), 145.8(C, triazol), 169.1-171.2 (24×C, AcO).

HRMS (ESI): m/z calcd for C₁₀₆H₁₄₅N₃O₆₄SNa₂ [M+2Na]²⁺: 1280.8844, found:1280.8864.

i. NaOMe, MeOH, rt, ii. Amberlite IR120 (H)

Example 32 Compound 16′

According to the general procedure B, using the derivative 15′ (55 mg,0.029 mmol) as starting material, the derivative 16′ was obtained afterlyophilization (39 mg, 0.026 mmol, 89%) as an amorphous white solid.

[α]_(D)=+161 (c=1.12, MeOH)

¹H NMR (400 MHz, D₂O) δ=1.14-1.74 (10H, m), 2.77 (2H, m, H-1′), 3.15(1H, bd, J_(6a,6b)=11.8 Hz, H-6a thioglycoside), 3.38-4.18 (51H, m),5.11 (1H, d, J=3.5 Hz, H-1 CD), 5.17 (5H, m, H-1 CD), 5.31 (1H, d, J=3.5Hz, H-1 CD), 5.42 (1H, d, J=1.1 Hz, H-1 thioglycoside), 8.04 (1H, s,triazol).

¹³C NMR (125 MHz, D₂O): δ=25.3 (CH₂), 27.4 (CH₂), 27.5 (CH₂), 28.2(CH₂), 28.4 (CH₂), 30.5 (CH₂, C-1′ thioglycoside), 51.5 (CH₂, C-6 CD),58.9-83.2 (9CH₂, 32CH), 85.2 (CH, C-1 thioglycoside), 101.9-102.3 (7×CH,C-1 CD), 123.8 (CH, triazol), 146.2 (C, triazol). HRMS (MALDI, DHB): m/zcalcd for C₅₈H₉₇N₃O₄₀SNa [M+Na]⁺: 1530.5261, found: 1530.5252.

D. Synthesis of mannosyl-C-heptylamides

a) ATMS, Et₂O BF₃, ACN, 0° C.→rt. b) Grubb's 2° generation cat., DCM,reflux. c) H₂, Pd(OH)₂, MeOH. d) NaN₃, DMF, 80° C. e) Carboxylic acid,HOBt, DIC, Ph₃P, THF, 0° C.→rt. f) NaOMe, MeOH.

Mannosyl-C-heptylamides are obtained from compound 23 through reactionwith allyl trimethylsilane (ATMS, step a)), olefin metathesis (step b)),hydrogenation (step c)), displacement of the mesylate using sodium azide(step d)), Staudinger-amide coupling (step e)) and deprotection (stepf)).

a) ^(t)BuOK, THF, 0° C. b) MsCl, Et₃N, DMAP, DCM, 0° C.→rt. c) 17′,Grubbs catalyst second generation, DCM, 43° C. d) i. H_(z), Pd/C, MeOH.ii. NaN₃, DMF, 80° C. e) i. Ph₃P, THF-H₂O, 60° C. ii. Isobutyricchloride, DMAP, DCM, rt. f) i. NaOMe, MeOH, rt, ii. Amberlite IR120 (H).

Example 33 Compound 17′

To a solution of 7-bromo-1-heptanol (2.00 mg, 8.439 mmol) in dry THF(240 mL), cooled at 0° C., was added tBuOK (2.08 g, 18.565 mmol). Afterstirring at 0° C. for 30 min, 10 ml of H₂O were added and the solventwas evaporated in vacuo.

To a solution of the crude in dry DCM (40 ml) was added MsCl (715 μl,9.283 mmol), Et₃N (1.76 ml, 12.659 mmol) and DMAP (100 mg). The mixturewas stirred for 3 h at rt, washed with saturated solution of NaHCO₃,concentrated under vacuum and the crude was purified by silica gelcolumn chromatography (Hexanes/EtOAc, 70:30) to give the product 17′(1.35 g, 7.089 mmol, 84%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ=1.43 (4H, m), 1.76 (2H, m), 2.07 (2H, m),3.00 (3H, s, MsO), 4.22 (2H, t, J=6.5 Hz), 4.93-5.04 (2H, m,CH₂-alkene), 5.79 (1H, m, CH-alkene).

¹³C NMR(100.6 MHz, CDCl₃): δ=24.8 (CH₂), 28.2 (CH₂), 28.9 (CH₂), 33.4(CH₂), 37.3 (CH₂), 70.0 (CH₃, MsO), 114.7 (CH₂, CH₂-alkene), 138.4 (CH₂,CH-alkene).

MS (CI, NH₃): m/z: [M+NH₃]⁺ 210

Example 34 Compound 19′

The Grubbs second-generation catalyst (206 mg, 0.242 mmol, 10% mol) wasadded under argon to a mixture of terminal alkenes 18′ (as described byPawel et al., J Am. Chem. Soc. 2008, 130, 2928-2929; 900 mg, 2.421 mmol)and 17′ (1.15 g, 6.053 mmol) in deoxygenated dry DCM (36 ml). Theresulting solution was stirred at reflux for 8 h. Removal of the solventin vacuo gave a brown oil, which could be purified by silica gel columnchromatography (Hexanes/EtOAc, 80:20) to give the product 19′ (703 mg,1.304 mmol, Z/E: 8/2, 54%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): major isomer 1.39 (4H, m), 1.74 (2H, m), 2.02(3H, s, AcO), 2.06 (3H, s, AcO), 2.08 (2H, m), 2.09 (3H, s, AcO), 2.12(3H, s, AcO), 2.42 (2H, m), 3.00 (3H, s, MsO), 3.89 (1H, m, H-5), 3.97(1H, m, H-1), 4.09 (1H, dd, J_(6a,6b)=12.1 Hz, J_(6a,5)=2.9 Hz, H-6a),4.22 (2H, t, J=6.6 Hz, H-7′), 4.32 (1H, dd, J_(6b,6a)=12.1 Hz,J_(6b,5)=6.0 Hz, H-6b), 5.18-5.28 (3H, m), 5.37 (1H, m, alkene), 5.57(1H, m, alkene).

MS (CI, NH₃): m/z: [M+NH₃]⁺ 554

HRMS (ESI): m/z calcd for C₂₃H₃₆O₁₂SNa [M+Na]⁺: 559.1819, found:539.1807.

Example 35 Compound 20′

The mixture Z/E of the metathesis product 19′ (458 mg, 0.854 mmol) and10% palladium on carbon (80 mg) in MeOH (15 mL) were stirred under ahydrogen atmosphere (1 atm) at room temperature for 4 h. The reactionmixture was filtered through a pad of Celite and the solvent wasevaporated in vacuo.

A solution of the crude in DMF (26 mL) was added NaN₃ (83 mg, 1.280mmol) and the resulting mixture was stirred at 70° C. overnight. Themixture was diluted with Et₂O and washed with H₂O and brine. The crudewas purified by silica gel column chromatography (Hexanes/EtOAc, 70:30)to give the azide 20′ (407 mg, 0.837 mmol, 98%) as a colorless oil.

[α]_(D)=+86.5 (c=0.91 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): 1.27-1.46 (10H, m), 1.59 (3H, m), 1.77 (1H, m),2.02 (3H, s, AcO), 2.05 (3H, s, AcO), 2.10 (3H, s, AcO), 2.13 (3H, s,AcO), 3.26 (2H, t, J=6.9 Hz, H-8′), 3.84 (1H, ddd, J_(5,4)=8.8 Hz,J_(5,6a)=6.1 Hz, J_(5,6b)=2.7 Hz, H-5), 3.94 (1H, ddd, J=10.0 Hz, J=4.6Hz, J=2.6 Hz, H-1), 4.09 (1H, dd, J_(6a,6b)=12.2 Hz, J_(6a,5)=2.8 Hz,H-6a), 4.30 (1H, dd, J_(6b,6a)=12.2 Hz, J_(6b,5)=6.1Hz, H-6a), 5.16-5.26(3H, m, H-2, H-3, H-4).

¹³C NMR(100.6 MHz, CDCl₃): δ=20.3 (CH₃, AcO), 20.36 (CH₃, AcO), 20.40(CH₃, AcO), 20.44 (CH₃, AcO), 25.6 (CH₂), 26.8 (CH₂), 28.7 (CH₂), 28.9(CH₂), 29.1 (CH₂), 29.3 (CH₂), 29.6 (CH₂), 51.3 (CH₂, C-8′), 62.7 (CH,C-6), 67.6 (CH), 69.6 (CH), 71.1 (CH), 71.2 (CH), 75.0 (CH, C-1), 169.4(C, AcO), 169.8 (C, AcO), 169.9 (C, AcO), 170.0 (C, AcO).

MS (CI, NH₃): m/z: [M+NH₃]⁺ 503

HRMS (ESI): m/z calcd for C₂₂H₃₅N₃O₉N₃Na [M+Na]⁺: 508.2265, found:508.2257

Example 36 Compound 21′

A mixture of 20′ (350 mg, 0.720 mmol) and 10% palladium on carbon (35mg) in MeOH (7 mL) were stirred under a hydrogen atmosphere (1 atm) atroom temperature for 10 h. The reaction mixture was filtered through apad of Celite and the solvent was evaporated in vacuo. To a solution ofthe amine crude in dry DCM (14 ml) was added isobutyric chloride (1141.080 mmol) and DMAP (264 mg, 2.160 mmol) at 0° C. under N₂ atmosphere.The mixture was stirred for 5 h at rt, concentrated under vacuum and thecrude was purified by silica gel column chromatography (DCM/MeOH, 90:10)to give the product 21′ (253 mg, 0.477 mmol, 66% from 20′) as acolorless oil.

[α]_(D)=+59.2 (c=0.75 in CHCl₃)

¹H NMR (300 MHz, CDCl₃): δ=1.11 (6H, d, J=6.9 Hz, 2×CH₃-isobutyricacid), 1.22-1.57 (13H, m), 1.74 (1H, m), 1.98 (3H, s, AcO), 2.02 (3H, s,AcO), 2.06 (3H, s, AcO), 2.10 (3H, s, AcO), 2.29 (1H, m, CH, isobutyricacid), 3.19 (2H, m, H-8′), 3.77 (1H, m, H-5), 3.87 (1H, ddd, J=10.0 Hz,J=4.6 Hz, J=2.6 Hz, H-1), 4.10 (1H, dd, J_(6a,6b)=12.1 Hz, J_(6a,5)=2.6Hz, H-6a), 4.04 (1H, dd, J_(6b,6a)=12.1 Hz, J_(6b,5)=5.9 Hz, H-6a),5.09-5.20 (3H, m, H-2, H-3, H-4), 5.53 (1H, bs, NH).

¹³C NMR(100.6 MHz, CDCl₃): δ=19.6 (2×CH₃, isobutyric acid), 20.2 (CH₃,AcO), 20.65 (CH₃, AcO), 20.67 (CH₃, AcO), 20.9 (CH₃, AcO), 25.2 (CH₂),26.7 (CH₂), 28.3 (CH₂), 28.9 (CH₂), 29.0 (CH₂), 29.2 (CH₂), 29.6 (CH₂),35.6 (CH, isobutyric acid), 39.2 (CH₂, C-8′), 62.6 (CH, C-6), 66.8 (CH),69.0 (CH), 69.9 (CH), 70.8 (CH), 75.2 (CH, C-1), 169.6 (C, AcO), 169.9(C, AcO), 170.3 (C, AcO), 170.6 (C, AcO), 176.8 (C, amide).

MS (CI, NH₃): m/z: [M+H]⁺ 530

HRMS (ESI): m/z calcd for C₂₆H₄₄0₁₀N [M+H]⁺: 530.2959, found: 530.2955.

Example 37 Compound 22′

According to the general procedure B, using the amide 21′ (50 mg, 0.094mmol) as starting material, the derivative 22′ was obtained afterlyophilization (33 mg, 0.091 mmol, 97%) as an amorphous white solid.

[a]_(D)=+26.6 (c=0.81 in MeOH).

¹H NMR (300 MHz, MeOD): δ=1.12 (6H, d, J=6.9 Hz, 2×CH₃-isobutyric acid),1.31-1.79 (14H, m), 2.44 (1H, m, CH-isobutyric acid), 3.17 (2H, q, J=6.3Hz, C-8′), 3.42 (1H, m, H-5), 3.61-3.89 (6H, m), 7.85 (1H, bs, NH).

¹³C NMR (100.6 MHz, MeOD): δ=19.9 (2×CH₃, 2×CH₃-isobutyric acid),26.9-30.5 (7×CH₂), 36.3 (CH, CH-isobutyric acid), 40.2 (CH₂, C-8′), 63.1(CH, C-6), 69.3 (CH), 72.8 (CH), 73.1 (CH), 75.5 (CH), 78.9 (CH, C-1),179.9 (C, amide).

MS (CI, NH₃): m/z 362 [M+H]⁺

HRMS (MALDI, DHB): m/z calcd for C₁₈H₃₅O₆NaN [M+Na]⁺: 384.2357, found:384.2354.

Example 38 Adhesion Ability of Adherent-Invasive E. coli to IntestinalEpithelial Cells in Presence of Monovalent Compounds: Pre-, Co- andPost-Incubation Experiments. Bacterial Strain and Cell Line

E. coli strain LF82 was isolated from a chronic ileal lesion of apatient with Crohn's disease (CD). Bacteria were grown routinely inLuria-Bertani (LB) broth overnight at 37° C. Intestinal epithelial cellsT84 derived from colonic adenocarcinoma were maintained in an atmospherecontaining 5% CO2 at 37° C. in DMEM/F12 (50/50) medium supplemented with10% (v/v) heat-inactivated fetal calf serum (FCS), 1% L-glutamine, 100000 U.1⁻¹ penicillin, 100 mg.1⁻¹ streptomycin, 25 μg.1⁻¹ amphotericin B.

Adhesion Ability of Adherent-Invasive E. coli to Intestinal EpithelialCells in Presence of Monovalent Compounds.

T84 were seeded in 48-well plates at a concentration of 1.5×10⁵ cellsper well and grown for 48 h. AIEC LF82 bacteria were incubated 1 h withmonovalent compounds prior the cell infection (pre-incubation protocol)or they were added simultaneously onto the cells (co-incubationprotocol) in complete medium without antibiotics, containing heatinactivated fetal calf serum (FCS). Monovalent compound 10 was tested ata dose of 100; 10; 1 (and 0.1) μM, compound 5 was tested at a dose of500; 100; 10 and 1 μM and D-mannose was tested at a dose of 10 000; 1000; 100 or 10 μM. Cells were infected with AIEC LF82 bacteria at amultiplicity of infection (MOI) of 10 bacteria per cell for 3 h at 37°C.

For the post-incubation protocol, monovalent compounds (same doses thanin the pre- and co-incubation assays) were incubated with cells for 3 hafter bacterial infection. A washing step was realized before thispost-incubation to eliminate non-adherent bacteria.

Monolayers were washed in phosphate-buffered saline (PBS; pH 7.2) andcells were then lysed with 1% Triton X-100 in deionized water. Sampleswere diluted and plated onto Luria Bertani agar plates to determine thenumber of colony-forming units (CFU) recovered from the lysedmonolayers. Results were expressed as percentages of residual adhesion,considering adhesion level of AIEC LF82 without mannosides treatment as100%.

Results

D-mannose, compounds 5 and 10 were assessed as putative inhibitors tocompete the interaction of CEACAM6 expressed by T84 intestinalepithelial cells with the adhesin FimH of AIEC bacteria following threedifferent protocols: pre-, co-and post-incubation experiments (FIG. 1).

For co-incubation experiments, results clearly indicated that monovalentcompound 10 possessed the best inhibitory effect, with a 50-foldincreased potency in comparison with the compound 5 and a 100-foldincreased potency in comparison with D-Mannose. Significant decreases inthe bacterial adhesion levels were obtained at 10 μM for compound 10, at500 μM for compound 5 and at 1 000 μM for D-Mannose. Using thepre-incubation protocol, D-mannose showed a significant inhibitoryeffect on the bacterial adhesion at 100 μM, whereas similar results thanthose observed with the co-incubation protocol were obtained forcompounds 5 and 10. Finally, in post-incubation experiments, D-mannosedecreased adhesion at a high dose of 10 mM, compound 5 was not able todecrease bacterial adhesion even at 500 μM, and compound 10 showed asignificant inhibitory effect at 100 μM. These data indicated thatmonovalent compound 10 is a good inhibitor to detach bacteria adheringto intestinal epithelial cells at a dose of 100 μM.

Example 39 Adhesion Ability of Adherent-Invasive E. coli Strains toIntestinal Mucosa of Transgenic Mice Expressing CEACAM6 in the Presenceof Monovalent Compounds Bacterial Strain and Transgenic Mouse Model

E. coli strain LF82 was isolated from a chronic ileal lesion of apatient with Crohn's disease (CD). Bacteria were grown routinely inLuria-Bertani (LB) broth overnight at 37° C.

The transgenic mouse model CEABAC10 expressing the human CEACAM6 proteinis available in the UMR Inserm/Université d'Auvergne 1071 led byProfessor Arlette Darfeuille-Michaud at Clermont-Ferrand. This model isparticularly suitable to mimic the abnormal colonization of gut mucosaby AIEC bacteria through the interaction of CEACAM6 abnormally expressedin the ileal mucosa of Crohn's disease and FimH adhesin of AIEC.

Adhesion Assays of Adherent-Invasive E. coli Strains to Colonic Loopsfrom CEABAC10 Mice in Presence of Monovalent Compounds.

Three colonic loops were performed in anesthetized CEABAC10 mice. Avolume of 100 μl of a bacterial suspension containing 2.5×10⁷bacteria/mL in the presence or absence of monovalent compounds wasinjected into the loops (here, compound 10 at a concentration of 100μM). After an incubation period of 4 h, mice were euthanized and eachloop was longitudinally opened, extensively washed in phosphate bufferand homogenized to numerate adherent LF82 bacteria. Bacterial adhesionlevels were expressed as colony forming units (CFU) per gram of colonictissue in the FIG. 2 (100% corresponds to the LF82 adhesion in absenceof any compound).

Results

A-two fold decrease in the number of LF82 bacteria adhering to colonicmucosa was observed in the presence of the monovalent compound 10 at aconcentration of 100 μM (FIG. 2).

Example 40 Effect of Orally Administered Monovalent Compounds toAdherent-Invasive E. coli LF82-infected transgenic mice expressingCEACAM6 Bacterial Strain and Transgenic Mouse Model

E. coli strain LF82 was isolated from a chronic ileal lesion of apatient with Crohn's disease (CD). Bacteria were grown routinely inLuria-Bertani (LB) broth overnight at 37° C. The transgenic mouse modelCEABAC10 expressing the human CEACAM6 protein is available in the UMRInserm/Université d'Auvergne 1071 led by Professor ArletteDarfeuille-Michaud at Clermont-Ferrand. This model is particularlysuitable to mimic the abnormal colonization of gut mucosa by AIECbacteria through the interaction of CEACAM6 abnormally expressed in theileal mucosa of Crohn's disease and FimH adhesin of AIEC.

AIEC colonization assessment in CEABAC10 mice treated with monovalentcompounds.

To mimic curative treatment, compounds were analyzed for theiranti-adhesive effect on a pre-established LF82 colonization in CEABAC10mice. CEABAC10 mice were given 0.5% of DSS in drinking water. Two dayslater, mice were treated per os with streptomycin sulfate, 5 mg/mouse.Twenty four hours later, (corresponding to day “0”), a five-hour cultureof AIEC LF82 bacteria in LB broth was concentrated to reach 5×10⁹bacteria/mL and was administered by gavage 2 h after the intragastricadministration of cimetidine at 50 mg/kg in order to ablate gastricsecretion. Oral administration of monovalent compounds at a range from 1to 1000 μg/mouse (=0.04 to 40 mg/kg) was realized 2 h after LF82infection. A second administration of the compounds was realized 18 hlater (cimetidine was also given 2 h before administration of thecompounds). Body weight and signs of colitis were followed for 4 days.Stools were collected from day 1 to day 4 post-infection to assessbacterial colonization. Mice were euthanized at day+4 and the entireintestine was collected to assess the number of AIEC bacteria associatedwith the gut mucosa, to measure pro-inflammatory cytokine secretion, tomeasure myeloperoxidase activity as indicator of neutrophil infiltrationin the intestinal tissue, to determine the disease activity index and toestimate histological damages of the mucosa.

Similar protocol was realized in testing a prophylactic administrationof the compounds (administration of similar doses of monovalentcompounds 5 h before infection). Compounds were compared for theirefficacy, depending on the dose and on the preventive or curativeeffect. To analyze whether the inhibitory effects could be related totoxicity effects, the absence of cell death of intestinal epithelialcells or bacteria was assessed at the highest dose of each compound.

CEABAC10 mice were infected with 10⁹ bacteria at day 0 (DO) and thenorally treated two times with 10 mg/kg of compounds 5 and 10 (“curativetreatment”). Body weight was followed during 3 days before LF82infection and until day 4 post-infection. Bacterial loads in feces andsigns of colitis were followed at day 1, 3 and 4 after infection as wellas the severity of colitis, assessed by establishment of the DiseaseActivity Index score (DAI). The numbers of bacteria associated to theintestinal mucosa were assessed at day 4 post-infection.

Intestinal tissues were sampled to measure the levels ofpro-inflammatory cytokines and to analyze damages of mucosa (HESstaining of colonic slices). Finally, spleen were collected andweighted.

Results

The body weight mean of the LF82-infected mice strongly decreasedbetween day 0 and day 4 post-infection, compared to the non-infectedgroup. LF82-infected mice treated with compound 5 or 10 did not show anydecrease in the body weight (FIG. 3). Compared to LF82-infected mice,LF82-infected mice treated with monovalent compounds 5 or 10 showed verylow DAI scores at day 3 and 4 post-infection, similar to that ofnon-infected mice (FIG. 4D). The LF82 colonization levels were stronglydecreased in the feces of LF82-infected mice treated with 5 and 10 (withless than 10⁴ bacteria/g of feces), in comparison with LF82-infected butnon treated mice (more than 10⁶ bacteria/g of feces) (FIGS. 4A, 4B and4C). Similar decreased colonization in the presence of compounds 5 and10 was observed for the number of bacteria associated to the ileum andthe colon (0 CFU/g of intestinal tissue) compared to 5×10³ and 1×10⁴CFU/g of tissue for ileum and colon, respectively, in the absence of anycompounds (FIG. 5). Compared to the non-infected mice, increased spleenweight was observed in LF82-infected mice. This was no longer observedwhen mice were treated with monovalent compounds 5 and 10 (FIG. 6).Finally, in that infection model, LF82 was able to increase the levelsof pro-inflammatory cytokines IL-23, KC and TNF-α secreted, compared tonon-infected mice. When mice were treated with monovalent compound, 5and 10 the levels of pro-inflammatory cytokines secreted were decreasedcompared to non-treated mice. Decreases were significant for the threeIL-23, KC and TNF-α cytokines in the presence of compound 10 but not inthe presence of compound 5 (FIG. 7).

Example 41 In Vitro Screening of Anti-FimH Molecules

Molecules were screened for their inhibition effect on the adhesion ofthe AIEC LF82 strain to intestinal epithelial T84 cells.

The molecules tested were the O-glycosides 10 and 5, the S-glycoside 16′and the C-glycoside 22′.

Post-Incubation Protocol with Undifferentiated T84 Cells:

The AIEC LF82 strain was incubated with T84 cells and then the testedmolecule was added.

The Protocol is as follows:

-   -   Cells: T84, 48h culture, in 48 wells plate at 1.5×10⁵        cells/well;    -   Bacteria: AIEC LF82 strain, Culture ON;    -   Inhibitor compounds in mother solutions (10, 20, 50 or 100 mM);    -   Measure the OD(620) of the bacterial culture;    -   Prepare the bacterial suspension at 6×10 ⁶ bact/mL in        DMEM/F12/SVF dec 10% medium;    -   Wash twice the cellular layer with PBS;    -   Add 250 μl/well of bacteria suspension, id. 1.5×10⁶ bact/well        (MOI=10);    -   Incubate 3 hours at 37° C.;    -   Prepare inhibitor compounds at the wished final concentration in        DMEM/F12/SVF dec 10% medium and filtrate at 0.2 l filter;    -   Wash 5 times the cellular layer with PBS;    -   Add 250 μL of inhibitor compounds/well;    -   Incubate 3 hours at 37° C.;    -   Wash 5 times the cellular layer with PBS;    -   Add 250 μL of Triton X-100 at 1%, incubate 5 min at room        temperature then add Triton in each well;    -   Take the entire content of each well and transfer it in an        Eppendorf tube of 1.5 mL;    -   Perform serial dilutions in physiological water: 50 μl of sample        in 450 μl of physiological water;

(NB: Prepare physiological water +2% D-mannose if difficulty met to getisolated colonies)

-   -   Spread 25 μl of dilution on LB-agar gelose;    -   Incubate overnight at 37° C.

For this experiment, all compounds have been tested at a finalconcentration of 100 μM.

Criteria of Evaluation:

The criteria of evaluation is the residual adhesion (level ofcolonization/decolonization of AIEC measured on cells) expressed inpercentage.

Results: Dose Effect with Tested Molecule at Different Concentrations:

Pre incubation experiments and post incubation experiments (FIG. 8)provide consistent results with respect to 10/22′ and 5/16′.

Example 42 In Vivo Testing of Anti-Adhesive Effect of Molecules on AIECLF82 Colonization in CEABAC10 Mice

Molecules tested: 10 (1 mg/kg and 10 mg/kg), 22′ (10 mg/kg), 16′ (10mg/kg), 5 (10 mg/kg) The aim was to test different compounds given peros to CEABAC10 mice infected by AIEC LF82 strains by assessing theirability to decrease bacterial colonization and related colitis.

Protocol:

-   -   Mice CEABAC10 (8 weeks-old males) were given DSS 0.5% in water        for all the time of experiment.    -   Two days later, mice were treated p.o. with Streptomycin        sulfate, 5 mg/mouse (in water).    -   The following day (=DO), LB broth was inoculated (1/100^(th))        with an ON culture of AIEC LF82 and incubated at 37° C. with        shaking in order to obtain a DO=0.5 or 0.6 maximum. Bacteria        were concentrated at 1.5×10¹⁰ bacteria/mL and 0.2 mL was        administered intra-gastrically to mice (=3×10⁹ bact/mouse) 2 h        after oral administration of cimetidine at 50 mg/kg in order to        ablate gastric secretion (6.25 mg/mL in water, 0.2mL/mouse).    -   Tested molecules were orally given twice at a dose of 250        μg/mouse (=10 mg/kg) or 25 μg/mouse (=1 mg/kg) in PBS, 2 h and        18 h after infection (cimetidine was given 2 h before each        administration of the compounds).    -   Body weight were followed for 3 (for ANRS) to 4 (for ANR3) days.    -   Stools were collected at day+1 (ANR3 and ANRS), day+3        post-infection (ANRS), day+4 post-infection (ANR3) to assess        bacterial colonization.    -   Mice were euthanized at day+4 for ANR3 and day+3 for ANRS and        entire intestine was collected to assess the bacterial        colonization at the mucosa (ileum+colon), to measure        pro-inflammatory cytokine secretions, to assess the neutrophil        infiltration into the tissues (myeloperoxidase activity), to        assess the disease activity index.    -   ANR3: Groups of male mice (32 mice in total):        -   A. Non-infected (NI) mice; n=8        -   B. LF82-Infected mice without treatment; n=8        -   C. LF82-Infected mice+10 at 10 mg/kg; n=8        -   D. LF82-Infected mice+5 at 10 mg/kg; n=8    -   ANRS: Groups of male mice (48 mice in total):        -   E. Non-infected (NI) mice; n=12        -   F. LF82-Infected mice without treatment; n=12        -   G. LF82-Infected mice+22′ at 10 mg/kg; n=12        -   H. LF82-Infected mice+16′ at 10 mg/kg; n=12

Criteria of Evaluation:

1. Body weight

2. Disease activity index (DAI)

3. Bacterial colonization in stools

4. Bacterial colonization at the mucosa

5. Pro-inflammatory cytokine secretions

6. Neutrophil infiltration into the tissues (myeloperoxidase activity)

Results:

The evolution of the weight of CEABAC10 transgenic mice uninfected orinfected with AIEC LF82 was followed after administration of variousmolecules to be tested (FIG. 9). Infection of mice with MEC LF82 leadsto a decrease in the weight of mouse. The administration of molecules10, 22′ and 16′ prevents weight loss induced by infection with the AIECLF82 strain (FIGS. 9A and 9B). This observation correlates withdecreased of disease activity index (DAT score) 3 days after infectionfollowing administration of molecules 10, 22′ and 16′ in mice infectedwith AIEC LF82 (FIG. 10). To assess the ability of molecules to reducethe colonization of the intestinal mucosa by AIEC strains, the amount ofAIEC bacteria present in the feces, which reflects the amount of AIECbacteria associated with intestinal mucosa, was measured. As control,one day post-infection, the amount of MEC bacteria present in feces wascomparable irrespective of the administration of molecules tested,indicating a similar level of colonization in all the batches from theexperiment. Interestingly, administration of molecule 22′ lead to adecrease in the amount of AMC LF82 bacteria in the feces of infectedmice at 3 and 4 days post-infection, showing the effectiveness of thesemolecules to decrease the ability of the MEC LF82 to colonize the mouseintestine (FIG. 11). In addition, the count of ALEC LF82 bacteriaassociated with ileal or colonic mucosa at 4 day post-infection showsthat the molecules 22′ and 16′ decolonized AIEC bacteria veryeffectively at the ileal and colonic mucosa (FIG. 12), Variousinflammatory parameters were measured at 3 or 4 days post-infection.First, the myeloperoxidase (MPO) activity, which reflects theinfiltration of the intestinal mucosa by neutrophils, was measured.Interestingly, administration of molecules 10, 5, 22′ led to a decreasein MPO activity (FIG. 13). In addition, the quantification of thepro-inflammatory cytokines IL23 (FIG. 14) and IL-Ibeta (FIG. 15) wasperformed at the level of mucosa from infected mice. The administrationof the molecules 10, 5, 16′ resulted in a reduction of the cytokine IL23level and administration of the molecules 10, 5 led to a decrease in therelease of IL I-beta.

All of these in vivo results obtained in the transgenic mouse modelCEABAC 10 infected with AIEC LF82 shows that different molecules testedeither reduced the activity of the disease (weight and score DAT), thelevel of colonization of mucosa or inflammatory parameters (MPO activityand production of pro-inflammatory cytokines), suggesting that thesemolecules are potentially useful in the treatment of Crohn's diseasepatients colonized by AIEC strains.

Example 43 Ex Vivo Protocol

The ex vivo model of explant cultures from human colonic mucosa is usedto examine the interactions of the AIEC strain LF82 with human colonicmucosa (controls) cells and the decolonization of AIEC from mucosa cellsthanks to the FimH antagonists molecules (treated).

Human Colonic mucosa explants. The mucosa is carefully stripped from theunderlying compartment. Fragments of 40 mg are maintained in cultureovernight in RPMI-BSA 0.01% supplemented with gentamicin to get rid ofcommensal bacteria, and fungizone washed twice in RPMI, and thenincubated for 4 h with or without bacterial cultures (LF82-GFP) in 2 mlculture medium without antibiotics. The explants are maintained at 37°C. in a 95% oxygen, 5% carbon dioxide humid atmosphere on a rockingplatform at low speed. In each experiment, at least three explants arecultured for each condition. The supernatants are centrifuged andaliquots are stored at −80° C. for further analysis.

Bacterial strains and media. The prototype AIEC strain LF82-GFP is used(UMR 1071 Inserm/Universite d'Auvergne, Clermont-Ferrand, France). Thestrains are stored at −20° C. in cryotubes. Before the experiments, thebacteria are cultivated on TS agar at 37° C. for 24 h after thawing. Foreach experiment, bacteria are subcultured in LB broth at 37° C. for 18hwith shaking. The bacteria are then centrifuged for 10 min at 800g. Thepellet is washed twice with sterile PBS, and the suspension is adjustedto 0.5×10⁸ or 0.5×10⁹ bacteria per milliliter, in culture medium(RPMI/BSA 0.01% without antibiotics).

The explant cultures, left to stabilize overnight in culture medium withantibiotics, were co-incubated with LF82-green fluorescent protein (GFP)(10⁸ or 10⁹ bacteria per explant) without antibiotics for 4 h. LF82bacteria, detected by immunoperoxidase using an anti-GFP antibody onparaffin sections, are found adhering to the apical pole of a fewepithelial cells of the surface and crypt base, scattered or sometimesfocally clustered.

Example 44 Pharmacokinetic Study Following Administration of 2 Compoundsby Oral and Intravenous Administration to Male Sprague Dawley Rats

These in vivo and analytical experiments are conducted to:

-   -   Estimate the plasma concentration level after oral and        intravenous administrations of 2 compounds to male Sprague        Dawley rats;    -   Calculate the bioavailability;    -   Estimate the amount of unchanged compounds in the faeces.

Two substances are tested (previously stored at room temperature in thedark).

For analysis, the molecules are dissolved in DMSO at 1 mg/mL.

Compounds Weight tube (mg) 10, 22′ 2 * 1 mg for the analytical part 15mg for the in vivo part

1. Analytical Test

Before the beginning of the in vivo part, an analytical test for eachcompound are performed in the two matrices.

The molecular and daughter ions are selected for each compound by directinfusion into the MS-MS system.

At least 8 point calibration standards are run using standard conditionswhich consist to LC-MS/MS system with C18 column after precipitation ofproteins before the start of the analytical test.

Blank rat faeces are homogeneized with 3 volumes of UHQ water untilobtention of a paste.

Then 100 μL of the homogenate are spiked with the molecules andprecipitated with 300 μL of acetonitrile.

For the plasma, 100 μL of blank rat plasma are directly spiked with thecompounds before being precipitate with 300 μL of acetonitrile.

The corresponding correlation coefficient (r) is calculated and shouldbe higher than 0.75 to continue with the in vivo test.

The concentration ranges tested are:

-   -   0.5 ng/mL to 1000 ng/mL for plasma,    -   4 to 2000 ng/g for faeces, corresponding to 1 to 500 ng/mL of        faeces homogenate.

2. In-Life Part

2.1. Characteristics, Housing and Handling of Animals

30 male Sprague Dawley rats around 6-7 week old are used.

At reception, the animals are housed in makrolon cages with stainlesssteel wire lids with catches. A label on each cage indicates thereception date, the rat strain, sex and weight.

Temperature and humidity are continually monitored. The animal roomconditions is kept as follows:

-   -   Temperature: 22° C.±2° C. Exceptionally, upper or lower values        can be tolerated.    -   Light/dark cycle: 12 h/12 h (07:00 h-19:00 h).

After administration and over the experiment duration, the animals areplaced individually in metabolic cages (tecniplast).

Animals have free access to food and water during the experiment.

2.2. Design

Volume of Dose Concen- administration Compounds Route vehicle (mg/kg)tration (mL/kg) 10, 22′ IV 100% DMSO 1 1 mg/mL 1 PO 100% DMSO 10 2 mg/mL5

2.3. Sampling

For each test substance

Admin- Blood Faeces istration sampling sampling Molecule route Rat nameTime Time 10, 22′ IV IV1, IV2,  5 min 0-24 h IV3 30 min  2 h  6 h 24 hPO PO4, PO5, 30 min 0-24h PO6  1 h  2 h  6 h 24 h

After administration, the animals are placed in individual metaboliccages in order to collect faeces samples during 24 hours.

2.4. Blood Sampling

At prescribed times, blood will be collected. Animals are brieflyanaesthetised with Isoflurane® using an anaesthetic system (ÉquipementVétérinaire Minerve) during blood samplings.

-   Site of collection: sinus retro-orbital using a capillary tube-   Volume of blood collected: 0.3 mL per time-point-   Anticoagulant: Heparin Lithium

Exact sampling times are noted for each blood sampling.

Blood samples are centrifuged at 2500 rpm at +4° C. (between 0 and 9°C.), the plasma is removed and placed into labelled polypropylene tubes.Individual plasma samples is stored frozen at −20° C. (targettemperature) until analysis.

3. Analysis

3.1. Analysis of plasma samples

100 μL of the plasma sample are taken and 300 μL of acetonitrile areadded. After protein precipitation, analysis are performed usingLC-MS/MS determination according to previous analytical test results.

3.2. Analysis of Faeces Samples

Faeces samples are collected over the 24 hours of the experiment.

They are precisely weighed and 3 volumes of UHQ water are added.

The mixture is homogeneized until obtention of a paste.

Then 100 μL of the homogenate are taken and extracted with 300 μL ofAcetonitrile.

Analysis is performed using LC-MS/MS determination according to previousanalytical test results.

3.3. Determination of the Concentrations

Concentrations of the samples are calculated directly from chromatogramsafter automatic integration by Analyst® 1.5.1 and expressed as ng/mL.

Mean plasma concentrations are calculated (when calculable, i.e. n≥2)using individual concentration and are expressed with the correspondingstandard deviation value and

$\left( {{{with}\mspace{14mu} {CV}\mspace{14mu} (\%)} = {\frac{SD}{Cmean} \times 100}} \right).$

variation coefficient (when calculable, i.e. n 3)

The individual plasma concentrations are tabulated for each rat andscheduled sampling time. Concentrations below the LLOQ are indicated byBLQ. All BLQ concentrations are substituted by zero for calculation ofthe descriptive statistics of the concentrations.

4. Results

The results is provided with plasma concentration/time curves, as wellas the tabulated concentrations results obtained for each plasma andfaeces time point.

Estimation of PK parameters is performed using Kinetica® (Version4.3—Thermo Electron

Corporation—Philadelphia—USA). An independent model method is used. Thefollowing parameters are estimated:

-   Cmax (ng/mL): maximal plasma concentration-   Tmax (h): first time to reach Cmax-   AUC_(t) (ng/mL*h): area under the plasma concentration-time curve    from administration up to the last quantifiable concentration at    time t-   Absolute bioavailability:

${F\mspace{14mu} (\%)}\; = {\frac{{AUC}\mspace{14mu} {{PO}/{dose}}\mspace{14mu} {PO}}{{AUC}\mspace{14mu} {{IV}/{dose}}\mspace{14mu} {IV}}*100}$

Example 45 Testing of Resistance to Mannosidases

Compounds are testing for degradation by intestinal enzymes likemannosidases, known to preferentially induce breakage between mannoseand O-linkage. To avoid such degradation, several analogues have beendesigned, for example 22′ (CH2-analogue of 10), 16′ (S analogue of 5).

Each compound is incubated with mannosidase and with or withoutinhibitors of mannosidase. Mass spectrometry experiments are performedto detect native and degraded compounds.

Example 46 In Vitro Toxicity Studies

The cytotoxic activity of compounds 10 and 22′ against normal cell linesusing MTS assay was determined.

Materials and Methods

Compounds 10 and 22′ were extemporaneously dissolved at 100 mM in waterto obtain a stock solution.

The final concentrations of compounds 10 and 22′ were 100 nM, 1 μM, 10μM, 100 μM and 1 mM within wells.

The cell lines that were used are detailed in the table hereafter:

Cell line Type Species Origin HUV-EC-C Umbilical vein Human Milliporeendothelial cells CCD-18Co Colon normal Human ATCC ® CRL-1459 ™fibroblast MRC-5 Normal fœtal Human ATCC ® CCL-171 ™ lung fibroblastPWR-1E Normal prostate Human ATCC ® CRL-11611 ™ cells

The 4 cell lines were plated at optimal density per well in 96-wellplates. Plates were incubated at 37° C. for 24 hours before treatment,in drug-free culture medium. Cell lines were then incubated for 96 hoursat 37° C. under 5% CO₂ with the 5 concentrations of compounds 10 or 22′in 1:10 dilution steps. Each concentration was done in triplicate.Control cells were treated with vehicle alone (water). At the end of thetreatment, the cytotoxic activity of compounds 10 and 22′ was assessedby MTS assay.

The in vitro cytotoxic activity of compounds 10 and 22′ was revealed bya MTS assay using tetrazolium compound (MTS,3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) and an electron couplingreagent named PMS (phenazine methosulfate).

The dose response for index of cytotoxicity (IC) is expressed asfollowing:

${IC} = {\frac{{OD}_{{drug} - {{exposed}\mspace{14mu} {wells}}}}{{OD}_{{vehicule} - {{exposed}\mspace{14mu} {wells}}}} \times 100}$

The OD values are the mean of 3 experimental measurements. IC₅₀represents the drug concentration required to obtain 50% of cellularcytotoxicity. The IC₅₀ determination values were calculated fromsemi-log curves.

Results

Cytotoxicity studies have shown that compounds 10 and 22′ do not presentan acute toxicity towards the above-mentioned four cell lines.

The values obtained for Docetaxel (control compound) are consistent withknown values of inherent toxicity, thus validating these experiments.

1. Method of treatment or prevention of inflammatory bowel disease, orCrohn disease or ulcerative colitis, comprising administering to asubject in need thereof an effective amount of a compound of thefollowing formula (I):

wherein: X represents NH, O, S or CH₂; n represents an integer comprisedfrom 3 to 7, or n being equal to 5; Y represents a group selected from:

Z representing O, S or NH; R representing: H, a linear or branched(C₁-C₇)-alkyl, or methyl, ethyl, isopropyl or isobutyl, a group offormula —(CH₂)_(i)—X′—(CH₂)_(j)—H, wherein X′ represents O, S or NH, iis an integer from 1 to 7, and j is an integer from 0 to 7, or a group—CH₂—O—CH₃, a linear or branched (C₂-C₇)-alkenyl, a linear or branched(C₂-C₇)-alkynyl, a (C₃-C₇) -cycloalkyl, a (C₅-C₇) -cycloalkenyl, a(C₃-C₇) -heterocycloalkyl, a (C₅-C₇) -heterocycloalkenyl, an aryl, saidaryl being an aromatic or heteroaromatic group, an alkyl aryl, whereinthe aryl is an aromatic or heteroaromatic group, a CO-(C₁-C₇)-alkyl, aCO-aryl, wherein aryl is an aromatic or heteroaromatic group, a CO₂H, aCO₂-(C₁-C₇)-alkyl, a CONH-(C₁-C₇)-alkyl, CF₃, adamantyl, CHRa-NH₂,wherein Ra represents the side chain of a proteinogenic aminoacid, acyclodextrin, or a cyclodextrin chosen from α-cyclodextrin (α-CD),β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and their derivatives, oralkylated α-cyclodextrins, alkylated β-cyclodextrins and alkylatedγ-cyclodextrins, or a cyclodextrin of one of the following formulae:

said (C₁-C₇) -alkyl, group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H, (C₂-C₇)-alkenyl, (C₂-C₇) -alkynyl, (C₃-C₇) -cycloalkyl, (C₅-C₇)-cycloalkenyl,(C₃-C₇)-heterocycloalkyl, (C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl,CO₂-(C₁-C₇)-alkyl, CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl andcyclodextrin being substituted or not by one or more substituent(s),each independently selected from: a linear or branched (C₁-C₇)-alkyl, alinear or branched (C₂-C₇)-alkenyl, a linear or branched(C₂-C₇)-alkynyl, a (C₃-C₇)-cycloalkyl, a (C₅-C₇)-cycloalkenyl, a(C₃-C₇)-heterocycloalkyl, a (C₅-C₇)-heterocycloalkenyl, an aryl, whereinthe aryl is an aromatic or heteroaromatic group an alkyl aryl, whereinthe aryl is an aromatic or heteroaromatic group, a CHO, a CO-(C₁-C₇)-alkyl, a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,a CO₂H, a CO₂-(C₁-C₇)-alkyl, a CONH-(C₁-C₇)-alkyl, a halogen selectedfrom the group comprising F, Cl, Br, and I, CF₃ OR_(a), wherein R_(a)represents: H, a linear or branched (C₁-C₇) -alkyl, a(C₃-C₇)-cycloalkyl, CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is anaromatic or heteroaromatic group, NR_(b)R_(c), wherein R_(b) and R_(c)represent independently from each other: H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl, CO-(C₁-C₇)-alkyl, or CO-aryl, wherein arylis an aromatic or heteroaromatic group, NO₂, CN, SO₃H or one of itssalts, or SO₃Na; and its pharmaceutically acceptable salts, providedthat when R represents CHRa-NH₂, then Y can only represent the followinggroup (a):


2. Method according to claim 1, comprising administering to a subject inneed thereof an effective amount of a compound formula (I), wherein R isR₁, R₁ representing: H a linear or branched (C₁-C₇)-alkyl, or isopropyl,a linear or branched (C₂-C₇)-alkenyl, a linear or branched(C₂-C₇)-alkynyl, a (C₃-C₇) -cycloalkyl, a (C₅-C₇) -cycloalkenyl, a(C₃-C₇) -heterocycloalkyl, a (C₅-C₇) -heterocycloalkenyl, an aryl, saidaryl being an aromatic or heteroaromatic group, an alkyl aryl, whereinthe aryl is an aromatic or heteroaromatic group, a CO-(C₁-C₇) -alkyl, aCO-aryl, wherein aryl is an aromatic or heteroaromatic group, a CO₂H, aCO₂-(C₁-C₇) -alkyl, a CONH-(C₁-C₇) -alkyl, CF₃, Adamantyl, CHRa-NH₂,wherein Ra represents the side chain of a proteinogenic aminoacid. 3.Method according to claim 1, comprising administering to a subject inneed thereof an effective amount of a compound formula (I), wherein Yrepresents:

of following formula (I-1a):

X and n being as previously defined, R₁ representing: H a linear orbranched (C₁-C₇)-alkyl, or isopropyl, a linear or branched(C₂-C₇)-alkenyl, a linear or branched (C₂-C₇)-alkynyl, a(C₃-C₇)-cycloalkyl, a (C₅-C₇)-cycloalkenyl, a (C₃-C₇)-heterocycloalkyl,a (C₅-C₇)-heterocycloalkenyl, an aryl, said aryl being an aromatic orheteroaromatic group, an alkyl aryl, wherein the aryl is an aromatic orheteroaromatic group, a CO-(C₁-C₇)-alkyl, a CO-aryl, wherein aryl is anaromatic or heteroaromatic group, a CO₂H, a CO₂-(C₁-C₇)-alkyl, aCONH-(C₁-C₇)-alkyl, CF₃, Adamantyl, CHRa-NH₂, wherein Ra represents theside chain of a proteinogenic aminoacid.
 4. Method according to claim 1,comprising administering to a subject in need thereof an effectiveamount of a compound formula (I), wherein Y represents:

of following formula (I-1b):

X and n being as previously defined, R₁ representing: H a linear orbranched (C₁-C₇)-alkyl, or isopropyl, a linear or branched(C₂-C₇)-alkenyl, a linear or branched (C₂-C₇)-alkynyl, a (C₃-C₇)-cycloalkyl, a (C₅-C₇)-cycloalkenyl, a (C₃-C₇)-heterocycloalkyl, a(C₅-C₇)-heterocycloalkenyl, an aryl, said aryl being an aromatic orheteroaromatic group, an alkyl aryl, wherein the aryl is an aromatic orheteroaromatic group, a CO-(C₁-C₇)-alkyl, a CO-aryl, wherein aryl is anaromatic or heteroaromatic group, a CO₂H, a CO₂-(C₁-C₇)-alkyl, aCONH-(C₁-C₇)-alkyl, CF₃, Adamantyl, CHRa-NH₂, wherein Ra represents theside chain of a proteinogenic aminoacid.
 5. Method according to claim 1,comprising administering to a subject in need thereof an effectiveamount of a compound formula (I), wherein Y represents:

of following formula (I-1c):

X, Z and n being as previously defined, R₁ representing: H a linear orbranched (C₁-C₇)-alkyl, or isopropyl, a linear or branched(C₂-C₇)-alkenyl, a linear or branched (C₂-C₇)-alkynyl, a(C₃-C₇)-cycloalkyl, a (C₅-C₇)-cycloalkenyl, a (C₃-C₇)-heterocycloalkyl,a (C₅-C₇)-heterocycloalkenyl, an aryl, said aryl being an aromatic orheteroaromatic group, an alkyl aryl, wherein the aryl is an aromatic orheteroaromatic group, a CO-(C₁-C₇)-alkyl, a CO-aryl, wherein aryl is anaromatic or heteroaromatic group, a CO₂H, a CO₂-(C₁-C₇)-alkyl, aCONH-(C₁-C₇)-alkyl, CF₃ Adamantyl, CHRa-NH₂, wherein Ra represents theside chain of a proteinogenic aminoacid.
 6. Method according to claim 1,comprising administering to a subject in need thereof an effectiveamount of a compound formula (I), wherein R is R₂, R₂ representing acyclodextrin, or a cyclodextrin chosen from α-cyclodextrin (α-CD),(β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and their derivatives, oralkylated α-cyclodextrins, alkylated β-cyclodextrins and alkylatedγ-cyclodextrins, or a β-cyclodextrin of the following formula:


7. Method according to claim 1, comprising administering to a subject inneed thereof an effective amount of a compound formula (I), wherein Yrepresents:

of following formula (I-2c):

X, n, Z and R₂ representing a cyclodextrin, or a cyclodextrin chosenfrom α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD)and their derivatives, or alkylated α-cyclodextrins, alkylatedβ-cyclodextrins and alkylated γ-cyclodextrins, or a β-cyclodextrin ofthe following formula:


8. Method according to claim 1, comprising administering to a subject inneed thereof an effective amount of a compound selected from the groupconsisting of:

and their pharmaceutically acceptable salts.
 9. Compound of thefollowing formula (I-0):

wherein: X represents NH, O, S or CH₂; n represents an integer comprisedfrom 3 to 7, or n being equal to 5; Y represents a group selected from:

Z representing O, S or NH; R representing: H a linear or branched(C₁-C₇)-alkyl, or methyl, ethyl, isopropyl or isobutyl, a group offormula —(CH₂)_(i)—X′—(CH₂)_(j)—H, wherein X′ represents O, S or NH, iis an integer from 1 to 7, and j is an integer from 0 to 7, or a group—CH₂—O—CH₃, a linear or branched (C₂-C₇)-alkenyl, a linear or branched(C₂-C₇)-alkynyl, a (C₃-C₇)-cycloalkyl, a (C₅-C₇)-cycloalkenyl, a(C₃-C₇)-heterocycloalkyl, a (C₅-C₇)-heterocycloalkenyl, an aryl, saidaryl being an aromatic or heteroaromatic group, an alkyl aryl, whereinthe aryl is an aromatic or heteroaromatic group, a CO-(C₁-C₇)-alkyl, aCO-aryl, wherein aryl is an aromatic or heteroaromatic group, a CO₂H, aCO₂-(C₁-C₇)-alkyl, a CONH-(C₁-C₇)-alkyl, CF₃, adamantyl, CHRa-NH₂,wherein Ra represents the side chain of a proteinogenic aminoacid, acyclodextrin, or a cyclodextrin chosen from α-cyclodextrin (α-CD),β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and their derivatives, oralkylated α-cyclodextrins, alkylated β-cyclodextrins and alkylatedγ-cyclodextrins, or a cyclodextrin of one the following formulae:

said (C₁-C₇)-alkyl, group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H,(C₂-C₇)-alkenyl, (C₂-C₇)-alkynyl, (C₃-C₇)-cycloalkyl,(C₅-C₇)-cycloalkenyl, (C₃-C₇)-heterocycloalkyl,(C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl, CO₂-(C₁-C₇)-alkyl,CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin beingsubstituted or not by one or more substituent(s), each independentlyselected from: a linear or branched (C₁-C₇)-alkyl, a linear or branched(C₂-C₇)-alkenyl, a linear or branched (C₂-C₇)-alkynyl, a(C₃-C₇)-cycloalkyl, a (C₅-C₇)-cycloalkenyl, a (C₃-C₇)-heterocycloalkyl,a (C₅-C₇)-heterocycloalkenyl, an aryl, wherein the aryl is an aromaticor heteroaromatic group an alkyl aryl, wherein the aryl is an aromaticor heteroaromatic group, a CHO, a CO-(C₁-C₇)-alkyl, a CO-aryl, whereinaryl is an aromatic or heteroaromatic group, a CO₂H, aCO₂-(C₁-C₇)-alkyl, a CONH-(C₁-C₇)-alkyl, a halogen selected from thegroup comprising F, Cl, Br, and I, CF₃, OR_(a), wherein R_(a)represents: H, a linear or branched (C₁-C₇) -alkyl, a(C₃-C₇)-cycloalkyl, CO-(C₁-C₇)-alkyl, or CO-aryl, wherein aryl is anaromatic or heteroaromatic group, NR_(b)R_(c), wherein R_(b) and R_(c)represent independently from each other: H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl, CO-(C₁-C₇)-alkyl, or CO-aryl, wherein arylis an aromatic or heteroaromatic group, NO₂, CN, SO₃H or one of itssalts, or SO₃Na; and its pharmaceutically acceptable salts, providedthat when R represents CHRa-NH₂, then Y can only represent the followinggroup (a):

with the proviso that said compound is not of the following structure:

and its salts.
 10. Compound according to claim 9, of the followingformula (I-1):

wherein: X represents NH, O, S or CH₂; n represents an integer comprisedfrom 3 to 7, or n being equal to 5; Y represents a group selected from:

Z representing O, S or NH; R₁ representing: H a linear or branched(C₁-C₇)-alkyl, or isopropyl, a linear or branched (C₂-C₇)-alkenyl, alinear or branched (C₂-C₇)-alkynyl, a (C₃-C₇)-cycloalkyl, a(C₅-C₇)-cycloalkenyl, a (C₃-C₇)-heterocycloalkyl, a(C₅-C₇)-heterocycloalkenyl, an aryl, said aryl being an aromatic orheteroaromatic group, an alkyl aryl, wherein the aryl is an aromatic orheteroaromatic group, a CO-(C₁-C₇)-alkyl, a CO-aryl, wherein aryl is anaromatic or heteroaromatic group, a CO₂H, a CO₂-(C₁-C₇)-alkyl, aCONH-(C₁-C₇)-alkyl, CF₃, adamantyl, CHRa-NH₂, wherein Ra represents theside chain of a proteinogenic aminoacid, said (C₁-C₇) -alkyl, (C₂-C₇)-alkenyl, (C₂-C₇) -alkynyl, (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl,(C₃-C₇)-heterocycloalkyl, (C₅-C₇) -heterocycloalkenyl, CO-(C₁-C₇)-alkyl,CO₂-(C₁-C₇)-alkyl, CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl and CO-arylbeing substituted or not by one or more substituent(s), eachindependently selected from: a linear or branched (C₁-C₇)-alkyl, alinear or branched (C₂-C₇)-alkenyl, a linear or branched(C₂-C₇)-alkynyl, a (C₃-C₇) -cycloalkyl, a (C₅-C₇)-cycloalkenyl, a(C₃-C₇)-heterocycloalkyl, a (C₅-C₇)-heterocycloalkenyl, an aryl, whereinthe aryl is an aromatic or heteroaromatic group an alkyl aryl, whereinthe aryl is an aromatic or heteroaromatic group, a CHO, aCO-(C₁-C₇)-alkyl, a CO-aryl, wherein aryl is an aromatic orheteroaromatic group, a CO₂H, a CO₂-(C₁-C₇)-alkyl, a CONH-(C₁-C₇)-alkyl,a halogen selected from the group comprising F, Cl, Br, and I, CF₃,OR_(a), wherein R_(a) represents: H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇) -cycloalkyl, CO-(C₁-C₇)-alkyl, or CO-aryl, whereinaryl is an aromatic or heteroaromatic group, NR_(b)R_(c), wherein R_(b)and R_(c) represent independently from each other: H, a linear orbranched (C₁-C₇) -alkyl, a (C₃-C₇) -cycloalkyl, CO-(C₁-C₇)-alkyl, orCO-aryl, wherein aryl is an aromatic or heteroaromatic group, NO₂, CN;and its pharmaceutically acceptable salts, provided that when R₁represents CHRa-NH₂, then Y can only represent the following group (a):


11. Compound according to claim 9, wherein Y represents:

said compound being of following formula (I-1a):

X, n and R₁ being as previously defined, or

said compound being of following formula (I-1b):

X, n and R₁ being as defined, or

Z being as defined, said compound being of following formula (I-1c):

X, n, Z and R₁ being as defined.
 12. Process of preparation of acompound of formula (I-0):

wherein: X represents NH, O, S or CH₂; n represents an integer beingequal to 3, 4, 5, 6 or 7, or n being equal to 5; Y represents a groupselected from:

Z representing O, S or NH; R representing: H a linear or branched(C₁-C₇) -alkyl, or methyl, ethyl, isopropyl or isobutyl, a group offormula —(CH₂)_(i)—X′—(CH₂)_(j)—H, wherein X′ represents O, S or NH, iis an integer from 1 to 7, and j is an integer from 0 to 7, or a group—CH₂—O—CH₃, a linear or branched (C₂-C₇)-alkenyl, a linear or branched(C₂-C₇)-alkynyl, a (C₃-C₇)-cycloalkyl, a (C₅-C₇)-cycloalkenyl, a(C₃-C₇)-heterocycloalkyl, a (C₅-C₇)-heterocycloalkenyl, an aryl, saidaryl being an aromatic or heteroaromatic group, an alkyl aryl, whereinthe aryl is an aromatic or heteroaromatic group, a CO-(C₁-C₇)-alkyl, aCO-aryl, wherein aryl is an aromatic or heteroaromatic group, a CO₂H, aCO₂-(C₁-C₇)-alkyl, a CONH-(C₁-C₇)-alkyl, CF₃, adamantyl, CHRa-NH₂,wherein Ra represents the side chain of a proteinogenic aminoacid, acyclodextrin, or a cyclodextrin chosen from α-cyclodextrin (α-CD),β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and their derivatives, oralkylated α-cyclodextrins, alkylated β-cyclodextrins and alkylatedγ-cyclodextrins, or a cyclodextrin of one of the following formulae:

said (C₁-C₇) -alkyl, group of formula —(CH₂)_(i)—X′—(CH₂)_(j)—H, (C₂-C₇)-alkenyl, (C₂-C₇) -alkynyl, (C₃-C₇) -cycloalkyl, (C₅-C₇)-cycloalkenyl,(C₃-C₇)-heterocycloalkyl, (C₅-C₇)-heterocycloalkenyl, CO-(C₁-C₇)-alkyl,CO₂-(C₁-C₇)-alkyl, CONH-(C₁-C₇)-alkyl, aryl, alkyl aryl, CO-aryl andcyclodextrin being substituted or not by one or more substituent(s),each independently selected from: a linear or branched (C₁-C₇)-alkyl, alinear or branched (C₂-C₇)-alkenyl, a linear or branched(C₂-C₇)-alkynyl, a (C₃-C₇)-cycloalkyl, a (C₅-C₇)-cycloalkenyl, a(C₃-C₇)-heterocycloalkyl, a (C₅-C₇)-heterocycloalkenyl, an aryl, whereinthe aryl is an aromatic or heteroaromatic group an alkyl aryl, whereinthe aryl is an aromatic or heteroaromatic group, a CHO, aCO-(C₁-C₇)-alkyl, a CO-aryl, wherein aryl is an aromatic orheteroaromatic group, a CO₂H, a CO₂-(C₁-C₇)-alkyl, a CONH-(C₁-C₇)-alkyl,a halogen selected from the group comprising F, Cl, Br, and I, CF₃,OR_(a), wherein R_(a) represents: H, a linear or branched (C₁-C₇)-alkyl, a (C₃-C₇)-cycloalkyl, CO-(C₁-C₇)-alkyl, or CO-aryl, wherein arylis an aromatic or heteroaromatic group, NR_(b)R_(c), wherein R_(b) andR_(c) represent independently from each other: H, a linear or branched(C₁-C₇) -alkyl, a (C₃-C₇)-cycloalkyl, CO-(C₁-C₇)-alkyl, or CO-aryl,wherein aryl is an aromatic or heteroaromatic group, NO₂, CN, SO₃H orone of its salts, or SO₃Na; and its pharmaceutically acceptable salts,provided that when R represents CHRa-NH₂, then Y can only represent thefollowing group (a):

with the proviso that said compound is not of one of the followingstructures:

and its salts, comprising the following steps: when Y represents:

reaction between a compound of formula (1a):

wherein Rp represents an ad hoc hydroxyl protecting group, and acompound of formula (2a):

wherein R₁ is a group R that is optionally protected by one or more adhoc protecting groups, in presence of triphenylphosphine, a couplingagent and optionally 1-hydroxybenzotriazole (HOBt) or1-hydroxy-7-aza-benzotriazole (HOAt), to obtain a compound of formula(3a):

cleavage of the Rp protecting groups and of the optional protectinggroups of R₁ in said compound of formula (3a), to obtain a compound offormula (I-0) wherein Y represents (a), of following formula (I-0a):

when Y represents:

reaction between a compound of formula (1b):

(1b), and a compound of formula (2b):

wherein R₁ is a group R that is optionally protected by one or more adhoc protecting groups, to obtain a compound of formula (3b):

cleavage of the Rp protecting groups and of the optional protectinggroups of R₁ in said compound of formula (3b), to obtain a compound offormula (I-0) wherein Y represents (b), of following formula (I-0b)

when Y represents:

reaction between a compound of formula (1c):

and a compound of formula (2b):

wherein R₁ is a group R that is optionally protected by one or more adhoc protecting groups, to obtain a compound of formula (3b):

cleavage of the Rp protecting groups and of the optional protectinggroups of R₁ in said compound of formula (3c), to obtain a compound offormula (I-0) wherein Y represents (c), of following formula (I-0c):